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11830 Westline Industrial Drive St. Louis, Missouri 63146
PEDIATRIC ENDOCRINOLOGY: THE REQUISITES IN PEDIATRICS Copyright © 2005 Mosby, Inc.
ISBN 0-323-01825-4
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Permissions may be sought directly from Elsevier Inc. Rights Department in Philadelphia, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, email:
[email protected] may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com, by selecting “Customer Support” and then “Obtaining Permissions.”)
Notice Pediatrics is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this publication. The Publisher
First Edition 2005. Library of Congress Cataloging-in-Publication Data Pediatric endocrinology: the requisites in pediatrics / [edited by] Thomas Moshang. — 1st ed. p. cm. — (The requisites in pediatrics series) ISBN 0-323-01825-4 1. Pediatric endocrinology. I. Moshang,Thomas. II. Series. [DNLM: 1. Endocrine Diseases—Child.WS 330 P3718 2004] RJ418.P346 2004 618.92′4–dc22 2004040241
Acquisitions Editor: Hilarie Surrena Developmental Editor: Kimberley Cox Project Manager: Jeff Gunning Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1
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To Mary Anne and my children, Beth, Tom, Peter, and Ali. And also to my mentors, Al Bongiovanni and Walter Eberlein, as well as all the Residents and Fellows who have taught me so much.
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Contributors
Craig A. Alter, M.D. Clinical Associate Professor, Department of Pediatrics, University of Pennsylvania School of Medicine; Pediatric Endocrinologist, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Neil Caplin, M.B.B.S., FRACP Assistant Professor, Department of Pediatrics, University of Washington School of Medicine; Attending Physician, Division of Endocrinology, Children’s Hospital and Regional Medical Center, Seattle,Washington Diva D. De León, M.D. Assistant Professor, Department of Pediatrics, University of Pennsylvania School of Medicine; Attending Physician, Division of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Robert J. Ferry, Jr., M.D. Assistant Professor of Pediatrics and Cellular and Structural Biology, University of Texas Medical School at San Antonio; Research and Training Director, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Texas Health Science Center at San Antonio; Attending Physician, Department of Pediatrics, Christus–Santa Rosa Children’s Hospital, and Department of Medicine, South Texas Veterans Administration Health Care System;Texas Medical Ranger, Alamo Medical Response Group, Medical Reserve Corps,Texas State Army Guard, San Antonio,Texas
Adda Grimberg, M.D. Assistant Professor, Department of Pediatrics, University of Pennsylvania School of Medicine; Attending Physician, Division of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Daniel E. Hale, M.D. Professor of Medicine, University of Texas Medical School at San Antonio; Chief, Division of Endocrinology and Diabetes, Department of Pediatrics, University of Texas Health Science Center at San Antonio; Senior Attending Physician, Department of Pediatrics, Christus–Santa Rosa Children’s Hospital, and Senior Physician, Department of Pediatrics, University Health System; Director, The Children’s Center, Texas Diabetes Institute, San Antonio,Texas Maria J. Henwood, D.O. Assistant Professor, Department of Pediatrics, The Ohio State University College of Medicine and Public Health; Attending Physician, Division of Endocrinology and Diabetes, Columbus Children’s Hospital, Columbus, Ohio Saraswati Kache, M.D. Clinical Instructor, Department of Pediatrics, Stanford University School of Medicine; Attending Pediatric Intensivist, Lucille Packard Children’s Hospital, Stanford, California
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CONTRIBUTORS
Lorraine E. Levitt Katz, M.D. Assistant Professor, Department of Pediatrics, University of Pennsylvania School of Medicine; Attending Physician, Division of Endocrinology, and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Howard E. Kulin, M.D. Professor of Pediatrics, Emeritus, Department of Pediatrics, Pennsylvania State College of Medicine, Hershey, Pennsylvania Mary M. Lee, M.D. Associate Professor, Department of Pediatrics, University of Massachusetts School of Medicine; Director, Division of Pediatric Endocrinology and Diabetes, UMass Memorial Health Care,Worcester, Massachusetts Peter A. Lee, M.D., Ph.D. Professor, Department of Pediatrics, Pennsylvania State College of Medicine;Attending Physicians and Chief, Division of Pediatric Endocrinology and Metabolism, Milton S. Hershey Medical Center, Hershey, Pennsylvania Sheela Magge, M.D. Fellow, Instructor in Pediatrics, University of Pennsylvania School of Medicine; Instructor, Division of Pediatric Endocrinology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Madhusmita Misra, M.D. Instructor in Pediatrics, Harvard Medical School; Assistant in Pediatrics and Assistant in Biology, Massachusetts General Hospital, Boston, Massachusetts
Thomas Moshang, Jr., M.D. Professor of Pediatrics, Emeritus, University of Pennsylvania School of Medicine; Senior Endocrinologist, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Wilma C. Rossi, M.D. Clinical Associate Professor, Department of Pediatrics, University of Pennsylvania School of Medicine; Pediatric Endocrinologist,The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Paul S. Thornton, M.B., B.Ch., MRCPI Medical Director, Department of Endocrinology and Diabetes, Cook Children’s Medical Center, Fort Worth,Texas Stuart A. Weinzimer, M.D. Assistant Professor, Department of Pediatrics,Yale University School of Medicine; Attending Physician, Yale–New Haven Medical Center, New Haven, Connecticut Weizhen Xu, M.D. Assistant Professor, University of Medicine & Dentistry of New Jersey Robert Wood Johnson Medical School; Physician, The Cooper Health System, Camden, New Jersey
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Foreword
What are the essential elements of pediatric endocrinology? How can this fascinating (and challenging) specialty, which involves recognizing and treating disorders of carbohydrate metabolism, growth, and thyroid function vital to health and life, be presented in an accessible manner? Will this book help those of us who are not endocrinologists in diagnosis, early treatment, and the decision to refer to our subspecialty colleagues if necessary? Fortunately, Thomas Moshang, in Pediatric Endocrinology: The Requisites in Pediatrics, has met the challenge posed in these questions with a clear, concise, and well-organized work. The book is divided into seven sections: Carbohydrate Disorders, Sexual Development, Growth, Thyroid, Adrenal Gland, Calcium, Phosphorus, and Bone and Vasopressin and Disorders of Fluids and Electrolytes. The most important aspects of each of these topics are the subjects of the chapters in that section. For example, Section 6 includes chapters on calcium regulation and hypocalcemic disorders, hypercalcemic disorders, and osteoporosis. Embryology, anatomy, and normal physiology are discussed in each of the sections where appropriate. Normal values and interpretation of abnormal values are outlined as well. As an example of the consistent relevance of the book’s content, Section 1, on carbohydrate disorders, includes an outstanding chapter on type 2 diabetes mellitus in children and adolescents, by Daniel E. Hale and Stuart A. Weinzimer. These authors point out that the
increasing incidence of type 2 diabetes mellitus is now considered a pediatric problem. The rising incidence is a “harbinger of an epidemic” of childhood obesity. I fear that it will be extremely important for primary care providers to understand the pathophysiology and feel comfortable with the treatment options for this disease for years to come. This second installment of The Requisites in Pediatrics fulfills the expectation for this series, which is to present information on the most common (and emerging) diseases in pediatrics and the required medical knowledge for students, nurse practitioners, resident physicians, and primary care physicians. I would like to thank Dr. Moshang and the contributors to this book for offering a useful, updated discussion of the most important topics in pediatric endocrinology. We hope you enjoy this second volume in the Requisites in Pediatrics series. Louis M. Bell, M.D. Patrick S. Pasquariello, Jr. Chair in General Pediatrics Professor of Pediatrics University of Pennsylvania School of Medicine Chief, Division of General Pediatrics Attending Physician, General Pediatrics and Infectious Diseases The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania
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Preface
Information and new knowledge pertaining to pediatric endocrinology, as in all of medical science, are expanding at an exponential rate. In fact, new hormones are being discovered to the degree where it is not yet clear how these hormones (such as leptin, resistin, adiponectin, and gherelin) are related to clinical disease. We know that many clinical disorders can be confirmed by analyzing specific genes, yet many of these gene studies are not available except in research laboratories. Specific hormones can be measured precisely in microunits, especially important in evaluating developmental changes in children. Yet despite all of the new technology, the genetic advances, and relevant discoveries, there is still a need for understanding the basic paradigms of clinical medicine. In medicine, the term requisites is interpreted as the basic knowledge that is necessary for practice or board review. This book was designed to be consistent with the premise of the other volumes in the Requisites in Pediatrics series—that there should be a series of books that provide required basic information important for pediatric residents, pediatricians, primary care physicians and nurse practitioners caring for children. In that context, this volume of the Requisites series provides a basic tutorial by each of the various authors in areas of pediatric endocrinology that are important for the care of children. Each chapter is to be read as if a trainee wishes to obtain basic information in a certain area in a tutorial fashion, not as a reference text or source book. Although many of the authors are involved in research, all are clinicians with a strong focus on pediatric endocrine care, and they wrote their chapters with clinicians in mind.
It is important to include discussion of disorders not previously thought to be within the purview of pediatric endocrinology, such as type 2 diabetes mellitus and osteoporosis.Type 2 diabetes mellitus, previously identified as “adult-onset diabetes mellitus,” is increasing in our adolescent patients in epidemic proportions. The chapter written by Daniel Hale and Stuart Weinzimer addresses not only the diagnosis and management of type 2 diabetes mellitus in adolescents but also some of the issues of increasing obesity in children.The technology and information for assessing bone density and osteoporosis are focused on the elderly, thereby making assessment and therapy in children difficult, as well as limiting management options, because of the lack of data in the pediatric population. In fact, even normative data for bone density based on age (because onset of puberty is variable in the normal adolescent population) may be inaccurate.These issues are still to be resolved, but clinicians caring for children with potential problems of bone formation should be aware of the many different issues as addressed in the section on osteoporosis. I appreciate the difficulty faced by academic clinicians writing chapters focused on requisite information: It is always easier to be exhaustively inclusive for fear of omissions. As the editor, I have the same concern that in selecting the requisite clinical issues important in pediatric endocrinology for clinicians, medical students, and residents, I have omitted important topics. Nevertheless, having made my choices, I wish to thank the various contributors for their efforts. Any important omissions are my responsibility, not that of the authors.
Thomas Moshang, Jr., M.D.
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Plate 1-1 Lipoatrophy of the buttocks secondary to insulin injections.
Plate 1-2 Lipohypertrophy in the upper arms due to repeated
This sequela is less common today with the use of human insulin. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
injections of insulin in the same area. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 2-1 Severe acanthosis nigricans associated with insulin resistance. The patient was a 15-year-old AfricanAmerican girl with type 2 diabetes mellitus and obesity. Note the thickened, vellous black areas on back and neck.
Plate 3-1 Infants with severe hyperinsulinemic hypoglycemia are born
Plate 3-2 The large hyperinsulemic hypoglycemic infant must be
very large for date, appearing extremely large generally.
distinguished from the infant with Beckwith-Wiedemann syndrome, who will have gigantism as well as other features including a large tongue and ear creases, as seen here. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
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Plate 4-1 Normal male penile and pubic hair development. A, Tanner 1 pubic hair and testicular and penile development. B, Early testicular development—Tanner 2 genital development but still Tanner 1 pubic hair. C, Tanner 2 pubic hair and Tanner 3 genital development. D, Tanner 3 pubic hair and genital development. E, Tanner 4 for both pubic hair and genital development. F, Tanner 5. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 4-3 Adolescent male gynecomastia. From 25% to 50% of adolescent males, especially heavy boys, will develop a mild degree of gynecomastia. Occasionally, as in this patient, the degree of gynecomastia may be severe enough to cause psychological problems, and surgical mammoplasty will be necessary. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 4-2 Normal female breast development, from Tanner stage 1 (prepubertal) to Tanner stage 5 (adult breast). (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 5-1 Precocious puberty. As seen in this 5-year-old patient with central precocious puberty, excessive weight is a not uncommon problem in girls with early puberty. 2
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Plate 5-2 Male precocious puberty. Precocious puberty is more likely in males than in females to be secondary to a central nervous system lesion. These two photographs demonstrate multiple café-au-lait spots with regular smooth borders (the adhesive bandage covers an injection site) and the changes characteristic of central precocious puberty in a boy with neurofibromatosis, who was found to have an optic glioma. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 5-3 McCune-Albright syndrome: café-au-lait macule. The triad in McCune-Albright syndrome consists of precocious puberty, polyostotic fibrous dysplasia, and café-au-lait macules. The macules are large, with irregular borders, and often are asymmetrical in location, as in this patient. This syndrome is due to an abnormally activated G protein mutation in the cyclic adenosine monophosphate (cAMP) system. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 5-4 A and B McCune-Albright syndrome: polyostotic fibrous dysplasia. These radiographs demonstrate the large cystic lesions in bone (especially in the radius) seen in this syndrome. In B, a spontaneous fracture through one of the cystic lesions in the femur can be seen.
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Plate 6-1 Microphallus. In this newborn boy, microphallus and
Plate 6-2 Delayed sexual development may be due to anorexia
cryptorchidism were secondary to panhypopituitarism. Microphallus is most frequently associated with gonadotropin deficiency. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
nervosa, as in this female patient. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 7-1 Ambiguous genitalia in a female infant. Virilization of the genitals, with an enlarged clitoris and fusion of the labia, can be seen. The underlying disorder was the 21-hydroxylase deficiency form of congenital adrenal hyperplasia. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.) 4
Plate 7-2 Ambiguous genitalia in a male infant. A small phallus, (with hypospadias) and incomplete fusion of scrotum, with both testes descended, can be seen. The underlying disorder was 3β-hydroxysteroid dehydrogenase deficiency.
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Plate 8-1 Turner syndrome: body habitus and other features. This
Plate 8-2 Turner syndrome: facial features. This 13-year-old patient
15-year-old patient demonstrates some of the classic features of Turner syndrome, including short stature, sexual infantilism, triangular facies, cubitus valgus (increased carrying angle of upper extremities), broad chest, and hypoplastic nipples. Many children with Turner syndrome will have only short stature, however, and need not have the phenotypic features pictured here. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
demonstrates the classic triangular facies with ptosis of the eyelids. She has sexual infantilism and short stature.
Plate 8-3 Achondroplasia in a 2-year-old child. At this age, the achondroplasia is represented by the short limbs, especially the proximal limbs. There is already a suggestion of lordosis; note also the disproportionately large head. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 8-4 Severe hypochondroplasia in a young adult (note the short limbs, especially the proximal limbs). Hypochondroplasia may be very mild and demonstrated only by careful measurements of extremities. The shortened limbs distinguish these patients from those with growth hormone deficiency, who are normally proportioned. As well, patients with hypochondroplasia have a normal bone age, whereas growth hormone–deficient patients have delayed skeletal maturation. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
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Plate 8-5 Leri-Weil syndrome. This short stature syndrome is due to a mutation or deletion of the SHOX gene and is characterized by short limbs, especially the distal limbs. There is often a dyschondrosteosis of the radius, with a Madelung deformity, as illustrated in this radiograph. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 9-1 A and B Goiter. The patient was a 15year-old girl with a large cystic goiter.
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Plate 9-2 Exophthalmos in a young woman with Graves disease.
Plate 10-1 Cushing syndrome in an infant due to an adrenal
(From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
carcinoma. At 3 months of age, the child shows the typical “moon facies” with acne and plethoric cheeks.
Plate 10-2 A and B Cushing syndrome in childhood secondary to an adrenal carcinoma. A, The patient’s appearance in a school photograph 1 year before onset of Cushing syndrome. B, The dramatic changes are clearly different from obesity.
Plate 10-3 A boy with Addison’s disease, pictured with his sister, showing the diffuse hyperpigmentation typical of the disorder.
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Plate 11-1 The short fourth and fifth metatarsals characteristic of pseudohypoparathyroidism may be less obvious in the hands of a child, as seen in the photograph. The abnormality is more readily appreciated on the radiograph. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
Plate 12-1 Williams syndrome. This patient has some of the phenotypic features of Williams syndrome; note the “elfin facies” with an upturned philtrum of the upper lip. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
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Plate 13-1 Osteoporosis. This radiograph shows the decreased bone density seen in many conditions of osteoporosis, such as osteogenesis imperfecta. The patient was a child with juvenile idiopathic osteoporosis. Decreased bone density is better quantified by either DEXA or quantitative CT. (From Wales JKH, Wit JM, Rogol AD: Pediatric Endocrinology and Growth, 2nd ed, Philadelphia, 2003, Saunders.)
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CHAPTER
1
Introduction Epidemiology Genetics Pathogenesis Pathophysiology Diagnosis and Differentiation of Type 1 Diabetes Mellitus Management of and Treatment Options for New-Onset Type 1 Diabetes Mellitus Diabetic Ketoacidosis Complications Medical Therapy of the Child with Type 1 Diabetes Mellitus General Principles Insulin Regimens Self-Monitoring and Problem-Solving Nutritional Management Exercise and Physical Fitness Psychological Aspects Medical Follow-up
Conclusions Major Points
INTRODUCTION Although the ancient Egyptian physicians first described polyuria, it was Aretaeus, a Greek physician and disciple of Hippocrates who lived in the second century C.E., who first coined the term diabetes, from the Greek word for “siphon.” He described the ailment as “a melting down of the flesh and limbs into urine,” as accurate a description of the disease as any in use today. Currently, diabetes may be defined as chronic hyperglycemia due to an absolute or relative deficiency of insulin. The criteria for the diagnosis of diabetes, as established by the National Diabetes Data Group and World Health Organization, are (1) a casual (at any time of day, regardless of timing of food intake) plasma glucose greater than 200 mg/dL in the presence of symptoms of
Type 1 Diabetes Mellitus in Children STUART A. WEINZIMER SHEELA MAGGE
diabetes, (2) fasting (>8 hours) plasma glucose greater than 126 mg/dL, or (3) a 2-hour post–75-gram glucose load glucose level greater than 200 mg/dL via oral glucose tolerance test. The oral glucose tolerance test is rarely useful in children. In the absence of obvious symptoms of diabetes (see Diagnosis section) or medications known to elevate the blood glucose (such as glucocorticoids), a casual or 2-hour postprandial blood glucose level greater than 200 mg/dL on two occasions is sufficient for the diagnosis. Diabetes encompasses several diseases with distinct genetic, pathophysiological, and therapeutic aspects. The predominant form of diabetes in children is type 1 (previously named insulin-dependent or juvenile) diabetes mellitus (T1DM), a state of absolute insulin deficiency caused by immunologically based destruction of the islets of Langerhans. Type 2 (non–insulin-dependent or adult-onset) diabetes, a state of relative insulin deficiency usually accompanied by insulin resistance, is becoming increasingly more common in the pediatric population and, hand-in-hand with obesity, represents an emerging public health problem. Less common varieties of diabetes include the MODY (maturity-onset diabetes of youth) phenomenon, a family of single-gene dominantly inherited disorders of regulation of insulin secretion, cystic fibrosis–related diabetes and other varieties related to pancreatic agenesis or damage, mitochondrial disorders, and pharmacologically induced forms of the disease. This section focuses on the genetics, epidemiology, pathophysiology, clinical presentation, and aspects of the treatment of T1DM only. Type 2 diabetes mellitus is discussed in a separate chapter.
EPIDEMIOLOGY Diabetes is the second most common chronic disease in childhood, after asthma, and occurs in 1 of every 1500 children by the age of 5 and in 1 of every 350 children by
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age 18. There are two peaks in age of presentation: the first occurs at ages 5 to 7 and the second occurs in early puberty. One third of people with T1DM do not present until adulthood, although T1DM rarely occurs after age 45. Diabetes affects boys and girls equally. T1DM is primarily a disease of whites of northern European, especially Scandinavian, background. The highest incidence rates of T1DM worldwide are found in Finland, Sweden, and Denmark, about 30 new cases annually per 100,000 population. For comparison, the annual incidence rate in the United States is about 12 to 15 per 100,000 population, whereas that in Africa is about 5 per 100,000 per year and that in east Asia is less than 2 per 100,000 per year. There are striking geographical differences related to diabetes incidence: countries located at a greater distance from the equator and with lower mean annual temperatures have greater incidence rates for diabetes, although whether this finding is related to genetic differences in populations or to exposure to certain infectious agents is unclear. Migrant studies show increased rates of diabetes in populations moving from areas of lower diabetes incidence to those with higher diabetes incidence. However, because general trends of migration are from poor, tropical, developing countries to more affluent, temperate countries in the Western world, confounding influences such as diet and lifestyle make the implication of certain geographical areas problematic.
GENETICS It has long been recognized that diabetes occurs more frequently in families with a previously affected member. First-degree relatives of an affected proband have an approximately 3% to 5% risk of developing diabetes, a 10-fold increase over that of the general population, and concordance rates for diabetes in identical twins are about 30% to 50%. It is clear that diabetes, as well as other autoimmune disorders such as Addison disease and thyroiditis, are associated with an increased frequency of certain human leukocyte antigens (HLAs) of the major histocompatibility complex (MHC). This system, located on chromosome 6, regulates the immune response and recognition of self from nonself through the expression of certain antigens on the cell surface. The inheritance of HLA antigen DR3 or DR4 increases the risk of development of diabetes approximately 3-fold, whereas the inheritance of both DR3 and DR4 confers about a 10- to 15-fold increase in risk. More than 90% of all whites with diabetes carry HLA antigen DR3 or DR4, although these alleles are present in more than 50% of the general white population. T1DM in African Americans is associated with the same HLA genes as in whites.
The homozygous absence of an aspartic acid residue at position 57 (Asp57) within the DQβ chain is associated with an approximate 100-fold risk of diabetes susceptibility, whereas individuals heterozygous for non-Asp57 also have an increased risk relative to Asp57/Asp57 homozygotes. The frequency of non-Asp57 is directly proportional to the incidence of T1DM within a given population. Similarly, the absence of arginine at position 52 of the DQα chain is also associated with increased susceptibility to T1DM. It is thought that the changes at positions 52 and 57 alter the tertiary structure of the HLA molecule, so that a normally closed “groove” is opened up, allowing greater access of the HLA antigen to T-cell receptors and triggering an immune response.
PATHOGENESIS The current model for the development of diabetes is that the susceptibility to the disease, rather than the disease itself, is inherited through specific genetic sequences with the MHC. This is followed by a triggering event, or “second hit,” that initiates the misdirected inflammatory process against the pancreatic islets. Recognition of β-cell stimulates T-lymphocyte activation, leading to the release of inflammatory cytokines, production of toxic free radicals, and β-cell killing, which in turn results in further β-cell antigen release and escalation of the immune process. T-cell infiltration of the islets is noted in pancreatic specimens of diabetics, akin to the infiltrates seen in other autoimmune disorders such as Hashimoto thyroiditis. There also is evidence that at disease onset, there is an alteration in the ratio between killer and helper T cells. The inflammatory process against the islets is accompanied by the development of serum antibodies that contribute to the inflammatory process. These islet cell antibodies (ICAs) are present in the serum of more than 80% of diabetic persons at diagnosis. The predominant autoantibody is GAD65, directed against the enzyme glutamic acid decarboxylase, which catalyzes the conversion of glutamate to γ-aminobutyric acid (GABA), but antibodies to insulin and other β-cell antigens (ICA512 or IA-2) are also seen. These autoantibodies may be detected in the blood years before the development of clinical diabetes, suggesting a smoldering, indolent, silent inflammatory destruction of β-cell mass that manifests clinically with carbohydrate intolerance when 90% of the β-cell mass is destroyed. The triggering event that leads to the destructive autoimmune process is thought to be a viral infection, either by molecular mimicry of a specific virus toward a β-cell antigen or through a nonspecific viremia. Certain
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viruses, such as rubella, mumps, coxsackievirus, and cytomegalovirus, may be directly toxic to pancreatic β-cells, whereas other viral infections may trigger the disease by producing a widespread, generalized immune response. The observations that breast-fed infants have lower incidences of diabetes and that many new-onset diabetic persons have antibodies to bovine serum albumin have led to concerns that early introduction of cow’s milk–based formulas may trigger diabetes, especially in susceptible individuals. Largescale prospective studies have been initiated to answer this question. Similarly, whether environmental toxins, such as nitrosamine compounds produced in the smoking of meat, are associated with increased diabetes risk, remains an unanswered question, although it is intriguing that populations with a typical Western diets, which are relatively antioxidant deficient, are associated with higher diabetes incidence than populations ingesting the higher antioxidantcontaining diets of the developing world. Antioxidant therapy for the prevention of diabetes, however, remains entirely speculative.
PATHOPHYSIOLOGY Insulin is an anabolic hormone that regulates the body’s balance of storage versus mobilization of body stores. It is stimulated by a rise in glucose levels in the peripheral bloodstream and, via a receptor-mediated mechanism, allows the uptake of glucose (through specific glucose transporters) into the cells of the peripheral tissues. In the liver, insulin stimulates glycogen synthesis and inhibits gluconeogenesis and glycogenolysis. Insulin also increases hepatic lipid synthesis from triglycerides and glycerol. In adipose tissues, insulin serves to favor lipid storage (lipogenesis). In skeletal muscle, insulin stimulates increased amino acid uptake, as well as protein and glycogen synthesis. Insulin action is inhibited by catecholamines, such as epinephrine, and by the other counterregulatory hormones, growth hormone and cortisol. In the absence of insulin, the body acts as if in the fasting state, despite being fed. Existing serum glucose cannot be used by peripheral tissues, because of the dependence of the peripheral tissue glucose transporters on insulin. Hepatic glycogenolysis and gluconeogenesis are stimulated, resulting in further hyperglycemia. As serum glucose levels exceed the renal threshold (180 mg/dL), an osmotic diuresis occurs, leading to significant urinary losses of fluids and electrolytes such as potassium, sodium, calcium, phosphorus, and magnesium. Continued glucose production along with decreased peripheral glucose uptake, combined with urinary water losses, leads to a slowly progressive dehydration and hyperosmolarity.
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The disruption in protein and fat metabolism also contributes to the metabolic destabilization. Insulin deficiency triggers lipolysis in adipose tissue, fatty acid oxidation in the liver, and proteolysis in muscle, leading to an accumulation of the ketones β-hydroxybutyrate and acetoacetate and subsequent metabolic acidosis. Progressive dehydration and acidosis stimulate production of the counterregulatory hormones epinephrine, growth hormone, and cortisol. These hormones further antagonize insulin action and thereby exacerbate hyperglycemia, catabolism, and metabolic acidosis through the stimulation of glycogenolysis, gluconeogenesis, lipolysis, and ketone production, perpetuating the vicious cycle.
DIAGNOSIS AND DIFFERENTIATION OF TYPE 1 DIABETES MELLITUS Classically, children with T1DM present with a triad of polyuria, polydipsia, and polyphagia. However, there is great variation within the spectrum and severity of presentation, and a wide differential diagnosis can exist. Furthermore, the fact that the initial presentation of T1DM is often triggered by an intercurrent illness can also confound the diagnosis. In children with T1DM, polyuria and compensatory polydipsia result once the renal threshold for glucose has been exceeded (at serum glucose concentrations of about 180 mg/dL), and glucosuria occurs. Hyperglycemia and the hyperosmolar state cause an osmotic diuresis, leading to the polyuria, polydipsia, and often enuresis. On presentation, these symptoms have often been present for several weeks. This is all the more true in infants and active adolescents, in whom it is difficult for parents to note the symptoms of excessive urination. Progressive insulin deficiency leads to weight loss, fatigue, and general malaise, as protein and fat stores are lost. As counterregulatory hormones increase and ketosis worsens, symptoms of acute illness develop, including nausea, anorexia, abdominal pain, and vomiting. At this point, the acute worsening of dehydration and acidosis may produce symptoms of lethargy, confusion, stupor, even coma, and the respiratory compensation for the metabolic acidosis produces hyperpnea, the deep-sighing Kussmaul respirations. Box 1-1 summarizes the typical symptoms present at diagnosis. Other important historical points that should be elicited at presentation include family history of diabetes or other autoimmune conditions (thyroiditis, Addison disease) and recent use of medications known to raise the blood sugar. The physical examination should focus on the state of hydration and include careful evaluation of heart rate and blood pressure and a description of mucous membranes, capillary refill, pulses, and warmth of extremities. A rough
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Box 1-1 Symptoms of Type 1 Diabetes
Box 1-2 Physical Findings in Type 1 Diabetes
Mellitus
Mellitus Dehydration Dry mucous membranes Decreased skin turgor* Delayed capillary refill* Tachycardia* Hypotension* Vulvovaginitis Fruity odor to breath* Kussmaul respirations* Ileus, guarding* Depressed level of consciousness*
Polyuria Polydipsia Polyphagia Weight loss Recurrence of enuresis in previously trained child Candidal vaginitis Lethargy Blurred vision Abdominal pain* Vomiting* Difficulty breathing* Obtundation* *
Indicative of diabetic ketoacidosis.
*
Indicative of diabetic ketoacidosis.
estimation of dehydration status (≈5%, 10%, or 20%) should be made to calculate the fluid deficit and facilitate rehydration therapy. A careful examination and written documentation of the neurological status are also critical, to serve as a baseline in case of deterioration in neurological status later in therapy. General physical examination should include respiratory and abdominal examinations, as well as a search for an intercurrent illness that may have served as the “trigger.” Evaluation of the thyroid for goiter and skin for hyperpigmentation allows for the diagnosis of potential comorbidities such as thyroiditis or Addison disease. Girls should be evaluated for the presence of candidal vulvovaginitis, and both boys and girls should have documentation of height, weight, and sexual maturity rating. The discovery of a “fruity” odor to the breath is characteristic of diabetic ketoacidosis (DKA), but significant ketosis may be present even in the absence of this finding. Box 1-2 summarizes common findings at diagnosis of T1DM. Appropriate laboratory studies begin with the measurement of serum blood glucose. As mentioned earlier, random “casual” blood glucose levels are indicated in the setting of a child with symptoms suggestive of diabetes. In the symptomatic child, blood glucose should be checked promptly; children should not be instructed to have a fasting blood glucose level measured the next day. In the obviously wellappearing child, minimal laboratory testing is required: electrolytes, blood urea nitrogen, and creatinine, along with a formal urinalysis for glucose and ketones, may suffice. In children with clinical evidence of more severe dehydration and/or other organ system signs, the evaluation should be expanded to include complete metabolic panel, blood count with differential, venous or arterial blood gas, and, in the setting of fever or shock, blood culture. Other studies depend on the clinical scenario and should be individualized.
A careful history, physical examination, and laboratory investigation should allow the diagnosis of diabetes mellitus to be deduced in a rapid, efficient manner. The presence of polyuria, polydipsia, and weight loss in a child should be considered T1DM until proved otherwise. The primary differential diagnosis for T1DM in children is urinary tract infection, due to the symptoms of excessive or frequent urination. If the symptoms of polydipsia and polyuria predominate, diabetes insipidus should be considered. However, formal urinalysis can easily differentiate the two conditions, as the urine of diabetes mellitus contains glucose, ketones, and osmotically active electrolytes, whereas the urine of diabetes insipidus is bland and dilute. If the presentation includes dehydration and vomiting, gastroenteritis should be considered, as should streptococcal pharyngitis and pneumonia. Pneumonia or asthmatic exacerbation may also be suggested in the setting of metabolic acidosis and Kussmaul respirations. In children presenting with fever, vomiting, and abdominal pain, appendicitis or other acute abdominal events may also be possibilities, a situation made more confusing by the fact that children in DKA often have leukocytosis. Other conditions in the differential diagnosis of T1DM include toxic ingestion, pelvic inflammatory disease in a sexually active adolescent, and, in any age, sepsis. Patients with persistent hyperglycemia may also present with various forms of fungal infections. Infants and toddlers may have thrush and/or diaper candidiasis, and adolescents may present with genital yeast infections. Patients and parents are often unaware that these symptoms are in any way related to diabetes. Thus, a careful genitourinary examination is necessary on admission. In a prepubertal child, the presence of candidiasis should always trigger blood glucose testing by the primary care physician. It should also be stressed that the diagnosis of diabetes
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requires measurement of blood glucose; the finding of glucosuria alone is not sufficient. Renal glycosuria, a benign condition in which the threshold for urinary excretion of glucose occurs even at normal blood glucose concentrations, may occasionally masquerade as diabetes in the child in whom routine urinalysis is performed in the absence of true symptoms of diabetes. Table 1-1 summarizes the differential diagnostic considerations in T1DM.
MANAGEMENT OF AND TREATMENT OPTIONS FOR NEW-ONSET TYPE 1 DIABETES MELLITUS The goals of management of the child with new-onset T1DM are metabolic stabilization of the child and education of the family to care for the child after the stabilization has been completed. Treatment of the newly diagnosed child with T1DM depends on the acuity of the illness at presentation: the ambulatory, well-appearing child without severe dehydration may be handled quite differently than the acutely ill, dehydrated patient with vomiting. It is still generally accepted that the newly diagnosed diabetic child requires acute hospitalization, in that
7
the frequent monitoring that is required cannot yet be accomplished in the ambulatory setting by an untrained family still recovering from the shock of the diagnosis. Small pilot projects by Chase and colleagues have, however, demonstrated that outpatient management of the new-onset diabetic patient may be accomplished in some situations. The development of diabetes in the sibling of a known patient may easily be managed in an ambulatory setting if the child is not acutely ill and the family is well trained in diabetes management. In the newly diagnosed patient without vomiting or ketoacidosis, initiation of subcutaneous insulin by injection is appropriate. In the case of a child with hyperglycemia alone, a dosage of approximately 0.3 to 0.5 unit/kg/day may suffice, whereas if ketosis is also present, a dosage of 0.7 unit/kg/day or more may be required. A child presenting in DKA and transitioning to subcutaneous insulin often requires 1 unit/kg/day or more. The management of a child presenting in DKA is discussed in a separate section. The total daily dose is divided into rapid- and intermediate-/long-acting insulin, typically Humalog (Lispro, Eli Lilly and Company, Indianapolis, IN) or Novolog (Aspart, Novo Nordisk, Bagsvaerd, Denmark) along with NPH, given in a three shot-per-day regimen. After calculating the
Table 1-1 Differential Diagnoses in Type 1 Diabetes Mellitus and Tests to Consider Clinical Findings
Differential Diagnosis
Tests/Interpretation
Polyuria, nocturia, enuresis
Urinary tract infection (UTI), benign nocturnal enuresis
Polydipsia
Psychogenic polydipsia, diabetes insipidus
Weight loss
Anorexia nervosa, gastrointestinal or chronic disease
Vomiting
Gastroenteritis, toxic ingestion, other metabolic disorders
Abdominal pain
Gastroenteritis, appendicitis, other intra-abdominal process
Hyperpnea
Pneumonia, asthma, anxiety
Hyperglycemia
Medication- or stress-induced hyperglycemia
Glycosuria
Benign renal glycosuria
Urinalysis demonstrates glycosuria with/without ketonuria characteristic of diabetes, instead of pyuria and other markers of UTI Urinalysis demonstrates glycosuria with/without ketonuria in diabetes, instead of low specific gravity (alone) Careful history should reveal behaviors and ideations characteristic of anorexia nervosa; plasma glucose diagnostic of diabetes Serum glucose and electrolytes in vomiting child reveal diabetes; electrolyte disturbances and acidosis without hyperglycemia suggest other metabolic disorders, requiring more directed testing Careful history and physical should elicit typical symptoms of diabetes and exclude surgical abdomen; measurement of serum glucose and urinalysis differentiates diabetes Kussmaul respirations (deep sighing breaths) suggest metabolic acidosis, whereas tachypnea suggests a primary respiratory disorder; no rales or wheezes; serum glucose and electrolytes characteristic of diabetes and metabolic acidosis May be mistaken for diabetes, although careful history does not demonstrate characteristic prodromal weight loss or urinary symptoms May be mistaken for diabetes; measurement of serum glucose differentiates diabetes from renal glycosuria
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total daily dose, approximately 50% is given as NPH and 15% is given as rapid-acting insulin before breakfast, approximately 10% is given as NPH and 15% as rapidacting insulin before dinner, and approximately 10% is given as NPH at bedtime. In toddlers, in whom meal intake is unpredictable, insulin may be administered after meals, by giving a set amount of long-acting insulin and dosing the rapid-acting insulin according to the prior carbohydrate intake (see description of carbohydrate counting later). In infants, generally only a long-acting insulin is given in a two or three shot-per-day regimen. Blood sugars are checked before meals, at bedtime, and at 2 to 3 AM (or before feedings in infants), and all urine output is checked for glucose and ketones by dipstick. For the child admitted to the hospital with only hyperglycemia and no ketosis, “touch-ups” of rapid-acting insulin can be given before meals in addition to the scheduled dose. Infants and toddlers may require only 0.5 unit of rapid-acting insulin to decrease the serum blood sugar by 100 mg/dL. In young school-age children, 1 unit may decrease the blood sugar by about 100 mg/dL, and in older school-age children, 75 mg/dL. In teenagers, in whom insulin resistance is typical, 1 unit may bring the blood sugar down by only about 30 to 50 mg/dL. These insulin “touch-ups” should generally be administered after the premeal or presnack blood glucose checks (to avoid hypoglycemia) and should be done with the goal to correct the blood sugar to approximately 120 mg/dL. In addition, it should be remembered that these rough guidelines should be individualized based on patient response. If a child also presents with ketosis, another treatment regimen, known as “sick day rules,” may be implemented. Blood glucose levels and urine ketones are checked every 2 hours. An additional 10% of the total daily dose of insulin is given as rapid-acting insulin every 2 hours until the urine ketones clear. This is continued even if the blood sugars are not elevated, as the presence of ketones indicates the need for supplemental insulin. Supplemental fluids should be given to restore intravascular fluid volume and hasten the excretion of ketones. In the child tolerating oral rehydration, a fluid “dose” of 1 ounce per year of age per hour serves as a rough guideline, of which the sugar content depends on the serum glucose. For blood sugar levels greater than 200 mg/dL, sugar-free fluids should be given; between 120 and 200 mg/dL, a mixture of sugar-free and sugar-containing fluids; and for less than 120 mg/dL, all sugar-containing fluids. “Sick day rules” are useful not only in the hospital setting but also to families at home trying to manage a diabetic child with an intercurrent illness. If emesis precludes normal oral intake, the intermediate- or longacting insulin should be discontinued, and small, frequent doses of short- or rapid-acting insulin only should be given.
Once the ketones have cleared and the child is tolerating an oral diet, the family may resume the normal routine. Newly diagnosed patients and their families should be taught carbohydrate counting. This allows dietary flexibility, as the child can adjust the rapid-acting insulin dose according to the mealtime or snack-time carbohydrate intake. A typical approximate starting ratio would be 0.5 unit of insulin for 15 to 30 grams of carbohydrate in the infant or toddler, 1 unit per 15 grams in the younger school-age child, and 1 unit per 10 grams in an adolescent. These ratios should be individually titrated based on the 2-hour postprandial blood glucose measurement. Before discharge, an assessment of the family’s overall level of coping and functioning should be made. Special situations, such as blended families or alternate/additional caretakers in the home, should be worked out before hospital discharge. Families typically experience shock and grief at the child’s diagnosis, but consideration should be made for referrals for psychosocial counseling if grief, anxiety, or depression appears to be excessive or interferes with diabetes education. On hospital discharge, the total daily insulin dose is typically decreased by 20% to 30%, as children are generally much more active at home and therefore require less insulin. Families are instructed to check for urine ketones if the blood sugar is greater than 240 mg/dL or if the child is sick. Close contact with the newly discharged patient is critical to monitor the safety and efficacy of the prescribed insulin regimen and the coping skills of the family.
DIABETIC KETOACIDOSIS DKA is a life-threatening, preventable complication of diabetes mellitus characterized by inadequate insulin action, hyperglycemia, dehydration, electrolyte loss, metabolic acidosis, and ketosis. It is associated with a significant mortality rate and is the most frequent cause of death in children with T1DM. Children whose diabetes has not yet been diagnosed may present with DKA, so the diagnosis must be considered in any child with confusion or coma of undetermined etiology. In children whose diabetes has already been diagnosed, DKA can usually be prevented by patient and family education, frequent monitoring of blood glucose and urinary ketones during intercurrent illness, adequate oral hydration, and supplemental insulin (“sick day rules”). Diabetic ketoacidosis is defined as a blood sugar level of greater than 240 mg/dL, ketonemia/ketonuria, and pH less than 7.3. The primary abnormality is insulin deficiency, which leads to hyperglycemia because of both decreased glucose utilization and increased gluconeogenesis. As glucose levels exceed the renal threshold of 180 mg/dL, an
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osmotic diuresis occurs, resulting in the loss of extracellular water and electrolytes and worsening of the hyperglycemia. Insulin deficiency also leads to accelerated lipolysis, with subsequent conversion of free fatty acids to β-hydroxybutyric and acetoacetic acids. This results in a metabolic acidosis. (Acetone is also formed and gives a fruity odor to the patient’s breath, but it does not contribute to the acidosis.) Potassium, primarily an intracellular ion, is transported out of the cell into the plasma in exchange for hydrogen and is lost in the urine. Thus, virtually all patients with DKA develop a “total body” deficiency of potassium, regardless of their serum potassium level. Phosphate, another predominantly intracellular ion, is handled similarly. Deficiency of 2,3-diphosphoglycerate, a phosphate-containing glycolytic intermediate in red blood cells that facilitates release of oxygen from hemoglobin, may contribute to the development of lactic acidosis complicating the ketoacidosis. Although insulin deficiency is the principal abnormality, elevated counterregulatory hormones (glucagon, cortisol, catecholamines, and growth hormone) contribute to both the accelerated gluconeogenesis and lipolysis. DKA is not difficult to recognize in a child with known diabetes who is dehydrated, hyperventilating, and obtunded. In the child whose diabetes has not yet been diagnosed, however, it may be confused with Reye syndrome, toxic ingestion (especially salicylate or alcohol), and central nervous system infection or trauma. Persistent vomiting may suggest gastroenteritis or, with abdominal pain, acute appendicitis or another intra-abdominal process. The diagnosis of diabetes (if not already established) is suggested by a history of polyuria, polydipsia, polyphagia, nocturia, or enuresis in a previously toilet-trained child. Weakness and unexplained weight loss may also be presenting features. When the diagnosis of DKA is suspected, an attempt should be made to identify precipitating causes (e.g., infection, stress, or noncompliance). In a child with known diabetes, it is important to review briefly the recent blood sugar history and to ascertain not only the usual insulin dosage but also the quantity and timing of the most recent injection. The physical examination should focus initially on the adequacy of the airway, breathing, and an assessment of the circulatory status (pulse, blood pressure, peripheral perfusion), degree of dehydration (including weight if possible), and mental status. Deep, rapid respirations (Kussmaul breathing) and a fruity odor to the breath are classic signs but are not present in every patient. A careful search should be made for a source of infection that may have precipitated the episode of DKA. Bedside determination of the blood glucose with a glucose monitoring device and evaluation of the urine for glucose and ketones should be performed as quickly as possible, and treatment should be initiated with-
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out waiting for the results of the laboratory assessment to become available. The laboratory evaluation of patients suspected to have DKA includes determination of the blood glucose, plasma or urinary ketones, serum electrolyte concentration, blood urea nitrogen (BUN), creatinine, osmolarity, and a baseline calcium and phosphorus. A baseline blood gas measurement should also be made to determine the pH and PCO2. Although venous blood gas measurements may suffice in milder episodes of DKA, an arterial blood gas measurement should be obtained in patients suspected to have incomplete respiratory compensation and/or those expected to require bicarbonate therapy (see later). If hyperlipidemia is present, the serum sodium concentration may be artifactually lowered. Similarly, the serum sodium is reduced approximately 1.6 mEq/L for each 100-mg/dL rise in glucose because of the reequilibration of the intracellular and extracellular compartments at a higher osmolarity. In the presence of ketones (and lactate), a large anion gap acidosis is present. The degree of elevation of the BUN and creatinine, as well as the hematocrit, may indicate the extent of dehydration (and the possibility of renal damage). The initial serum potassium may be low, normal, or high, depending on the degree of acidosis and the quantitative urinary losses. The acute management of DKA is directed at correction of the dehydration, electrolyte loss, hyperglycemia, and acidosis (Box 1-3). Initial fluid therapy is aimed at rapid stabilization of the circulation to correct impending shock but, as in other forms of hypertonic dehydration, too rapid fluid administration must be avoided. Fluid replacement in excess of 4 L/m2/24 hr has been associated with the development of potentially fatal cerebral edema in DKA. For this reason, an initial fluid bolus is usually advised to expand the vascular compartment and improve peripheral circulation, but once the patient has been stabilized, subsequent rehydration is accomplished with caution. Typically, one aims to correct the fluid defect gradually, over 36 to 48 hours. Gradual correction is particularly important in children at an increased risk of developing cerebral edema. This includes children with altered mental status, history of symptoms for longer than 48 hours, pH of less than 7.0, glucose of greater than 1000 mg/dL, corrected sodium of greater than 155 mEq/L, extreme hyperosmolality (>375 mOsm/L), or age younger than 3 years. A corrected sodium level that fails to rise with treatment may signify excessive free water accumulation and an increased risk of cerebral edema. Therefore, rehydration fluids should contain at least 115 to 135 mEq sodium chloride/L to ensure a gradual decline in serum osmolality and minimize the risk of cerebral edema. Early potassium replacement is also important, to correct the potassium depletion that occurs because of both the severe initial intracellular losses and the
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Box 1-3
Guidelines for Management of Diabetic Ketoacidosis
Insulin
Fluids
Sodium
Potassium
Glucose
Bicarbonate Clinical monitoring Laboratory monitoring
A continuous intravenous infusion of 0.1 unit/kg/hr is typical. For very young or severely acidotic, hyperosmolar patients, 0.05 unit/kg/hr may be initiated to prevent rapid changes during metabolic stabilization. In hyperglycemic, hyperosmolar, nonketotic coma (which is rarely seen in children except in some adolescents with type 2 diabetes), insulin may be withheld during the first several hours. A 10 to 20 mL of 0.9% saline/kg bolus to restore intravascular volume. Repeat as needed to treat shock. Base subsequent fluid administration on estimated degree of dehydration, and plan to replace deficit evenly over 48 hours. Na+ deficit at presentation generally resolves with administration of isotonic fluids during resuscitation phase. Measured [Na+] typically underestimates true Na+ levels due to effects of hyperglycemia. Calculation and assessment of true [Na+] over time may decrease risk of cerebral edema. + K deficit at presentation requires aggressive therapy. Replacement depends on serum [K+] at presentation; 20-60 mEq ( ¹⁄₂ as KCl and ¹⁄₂ as K+ phosphate) added to each liter of rehydration fluid is typical. Added to rehydration fluids once the blood glucose level falls 300 mg/24 hr or 200 μg/min), nephrotic syndrome, and end-stage renal disease (stage 5) occurs in about 30% to 40% of patients with diabetes of 30 years’ duration. Overt nephropathy is uncommon in children, but earlier stages of the disease may be seen in the pediatric diabetes population. The prevalence of microalbuminuria in children and adolescents is about 20% to 30% and, as in retinopathy, appears to depend on not only the duration of diabetes but also the number of years postpuberty. Diabetic neuropathy develops in about 50% of diabetics within 10 years of disease diagnosis, although clinically evident diabetic neuropathy is extremely rare in children. However, decreased vibration and light touch sensation as well as decreased nerve conduction velocity, indicative of peripheral neuropathy, may be detected in children using sensitive techniques. Autonomic neuropathy is also extremely rare in children with diabetes, although abnormal cardiac autonomic testing may be demonstrated. Autonomic dysfunction in diabetics has been implicated in increased risk of hypoglycemia unawareness and sudden death (“dead-in-bed” syndrome). Macrovascular disease and atherosclerosis are the major causes of death in adults with T1DM. Hypercholesterolemia and hyperlipidemia are frequently seen even in pediatric patients with T1DM, the extent of which is inversely proportional to the degree of metabolic control.
MEDICAL THERAPY OF THE CHILD WITH TYPE 1 DIABETES MELLITUS General Principles Optimal management of the child with diabetes requires an integrated approach, taking into account the overall level of functioning of the child and family, the nutritional and lifestyle patterns specific to that child, and attention to the overall developmental stages of childhood and adolescence. There is not just one appropriate insulin regimen or meal plan. The overriding principles are that the diabetes care plan should fit wherever possible into the surrounding home and school environments and that the primary childhood tasks of education, socialization, growth, and maturity should continue unhindered by the extra responsibilities that diabetes care entails. This potentially daunting task requires a multidisciplinary team, consisting of physicians, nurses, dietitians, and mental health professionals who are all trained and experienced in the nuances of diabetes care. Children with diabetes should be seen by the team at frequent intervals for assessment of glycemic control, growth, and development; evaluation for related disorders and complications; education, troubleshooting, and problem-
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solving; and screening for adjustment problems that may affect diabetes and/or the overall health of the child. The rationale for this intensive approach to diabetes care comes from the Diabetes Control and Complications Trial (DCCT), a national multicenter study designed to test the hypothesis that “intensive” diabetes management would be associated with fewer long-term complications of diabetes than “standard” therapy. At the time of the DCCT, standard diabetes therapy consisted of two injections of insulin daily, infrequent home testing of the blood glucose level, and basic nutritional and exercise counseling. Intensive management entailed at least three or four injections of insulin daily or use of continuous subcutaneous insulin infusion (CSII) via programmable portable pumps (“pump therapy”), frequent selfmonitoring of the blood glucose level through home glucose meter use, and frequent contact with the diabetes care team to adjust insulin dosages and the nutritional and exercise programs. In the DCCT study, intensive treatment in adults was associated with improvement in glycemic control (hemoglobin A1c [HbA1c] of 7.1% versus 9.0% in the standard group) and dramatically reduced incidence and progression of microvascular complications. The development and progression of retinopathy were reduced by 70%, whereas nephropathy was reduced by 35% and neuropathy was reduced by 30% to 70%. Significantly, there was an almost linear relationship between the HbA1c and the risk of complications. There was no real threshold effect: the risk decreased with each improvement in the HbA1c but remained elevated for any HbA1c value greater than normal. However, intensive control was also associated with a 3-fold increase in severe hypoglycemia and a 2-fold increase in obesity. The DCCT also demonstrated that intensive control was possible in adolescents. Intensively treated adolescents achieved a mean HbA1c of 8.1% (versus 9.8% in the standard group). Intensive control in adolescents was associated with a 60% reduction in the risk of retinopathy and a 35% reduction in the risk of nephropathy. As in adults, adolescents undergoing intensification of therapy were at a 3-fold risk of severe hypoglycemia and a 2-fold risk of obesity. It is worthwhile to note, however, that the benefits of intensive control persisted even after the conclusion of the trial. In a 4-year follow-up study of adolescents participating in the DCCT, despite equivalent HbA1c levels, subjects who had been intensively controlled during the DCCT period continued to have a 74% to 78% reduction in risk of worsening retinopathy and a 48% to 85% reduction in risk of nephropathy.
Insulin Regimens The goal of insulin therapy is to most closely approximate the requirements of the body for basal metabolism and meals with the use of exogenous subcutaneous injection.
13
In essence, the normally “closed loop” of the β cell, which senses the body’s minute-to-minute insulin requirements and matches it with insulin production and secretion, is replaced by the “open-loop” system of the home glucose meter and insulin syringe. Insulin has continued to evolve from an impure animalderived pancreatic extract with poorly predictable pharmacokinetics and pyrogenic tendency to a pure, recombinantly derived human protein with reliable activity profile and low antigenicity. Many types of insulin preparations are commercially available, with different onset, peak, and duration effects, to custom design an insulin regimen to suit the particular child or clinical need. Recently, very rapid-acting insulin analogues (Lispro, Eli Lilly and Company, Indianapolis, IN; and Aspart, Novo Nordisk, Bagsvaerd, Denmark) and one very long-acting, peakless insulin analogue (Glargine, Aventis Pharmaceuticals, Bridgewater, NJ) were developed. A list of available insulin preparations is given in Table 1-2. Before the DCCT, most children with diabetes were treated with two shots of insulin daily: a combination of short- and intermediate-acting insulin given approximately 30 minutes before both breakfast and dinner. The rationale for this approach is that the short-acting insulin (Regular) would “cover” the glycemic surge of breakfast and dinner meals and the intermediate-acting insulin (NPH, Lente) would “cover” the lunch meal and basal overnight requirements. Typically, the insulin dose would be split so that two thirds of the daily dose was given in the morning (one third of that as Regular and two thirds as NPH or Lente) and one third of the daily dose was given before dinner (half of that as Regular and half as NPH or Lente). Most children would require 0.7 to 1.0 unit/kg/day, less in younger children or those with recent onset, and frequently more in adolescents. Late-morning and late-evening hypoglycemia is a frequent complication of this regimen, as the peaks of NPH or Lente are highly variable. Additional snacks in the morning and late at night ameliorate the hypoglycemia but may predispose to weight gain. The desire for intensive insulin therapy, the justification for which was provided by the results of the DCCT, has been aided by the development of rapid-acting insulin analogues. The rapid-acting analogues more closely match the glycemic surges after meals and are associated with less frequent postprandial hypoglycemia. An additional benefit of the rapid-acting analogues is that meals may be eaten immediately after the injection. Most children are now treated with a mixed dose of rapid- and intermediate-acting insulin at breakfast and dinner and an additional injection of intermediate- or long-acting insulin at bedtime. However, many other combinations are possible, including one or two injections of very-long acting insulin (Ultralente, Eli Lilly and Company, Indianapolis, IN; or
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Table 1-2 Pharmacodynamic Properties of Common Insulin Formulations Category
Onset (hr)
Peak (hr)
Duration (hr)
0.25-0.5 0.25-0.5
0.5-1 0.5-1
3-4 3-5
0.5-1
2-4
4-8
2-4 3-4
4-10 6-12
12-24 12-24
4-6 2-4
6-12 NA
18-24 24+
0.5-1 0.5-1 0.25-0.5 0.25-0.5
2-8 2-6 1-2 1-2
12-24 12-24 12-24 12-24
Rapid-acting Insulin Lispro Insulin Aspart Short-acting Regular Intermediate-acting NPH Lente Long-acting Ultralente Insulin Glargine Premixed 70/30 (70% NPH/30% Regular) 50/50 (50% NPH/50% Regular) Mix 25 (75% NPH/25% Lispro) Novolog Mix (70% NPH/30% Aspart)
Glargine, Aventis Pharmaceuticals, Bridgewater, NJ) daily plus rapid-acting analogue with each meal or snack. Clearly, the most appropriate regimen depends on the schedule and desire of the child and family. CSII, or insulin pump therapy, has grown in popularity. Although programmable insulin pumps have been available for more than 20 years, technological advancements have made practical use feasible. Pump therapy more closely mimics the true physiological state, in that rapid-acting insulin is continuously infused at very low basal levels, with additional boluses for mealtime demands. Both the basal rates and bolus amounts are programmable. Multiple basal rates may be programmed, so that the normal early morning surge in blood glucose may be matched by an incremental increase in the insulin dose. Multiple studies in both adults and adolescents have demonstrated that CSII is associated with improvements in glycemic control, less weight gain, and less frequent hypoglycemia, and newer pump models assist in dose calculation for meals or hyperglycemia correction.
Self-Monitoring and Problem-Solving It should be readily apparent from the discussion of intensive insulin therapy that the safety and success of any insulin regimen are dependent on frequent monitoring of blood glucose levels. Intensive diabetes control would have been impossible without the development of inexpensive, accurate, easy-to-use home glucose meters. There are many brands of glucose meters that are commercially available,
most of which have similar reliability and accuracy to within about 10% of laboratory measurements. Older models used a glucose oxidase–impregnated reagent strip that, when exposed to a drop of blood, underwent a color change that could be assayed spectrophotometrically by the meter and converted to a numerical value based on known calibration standards. Newer models instead rely on a peroxidase system that generates a small electric current, which is then converted to a numerical value based on calibration standards. The newer meters are faster (results in 5 versus 45 seconds) and require less blood (0.1 versus 1.0 μL). The smaller blood volume requirement has allowed alternate site lancing (forearm, thigh, calf ), which may minimize discomfort and improve adherence to self-monitoring regimens. Children with diabetes should routinely test the blood glucose 4 times daily (before meals and before bedtime) and record the results in a log for later review by the family and diabetes care team. A target range is established, typically 80 to 120 mg/dL at breakfast and 80 to 150 mg/dL at other times of day but may be altered based on the age of the child and the ability of the family. Ideally, 80% of the blood glucose values should fall within the target range. Information gained from frequent testing is used to titrate insulin dosages according to need. For example, a regular pattern of prebreakfast hyperglycemia should prompt the family to increase the bedtime long-acting insulin dose incrementally over several days until the majority of prebreakfast readings fall within the target range, whereas frequent hypoglycemia during school may suggest reducing
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the morning rapid- or intermediate-acting insulin. Additionally, supplemental insulin doses may be given when blood glucose values outside the target range are discovered, according to a predetermined formula. For example, a younger child with a pre-dinner blood glucose of 240 mg/dL may be given 1 extra unit of rapid-acting insulin analogue to reduce the blood glucose by 100 mg/dL in addition to the usual insulin dose at that mealtime. Supplemental blood glucose testing should be performed before exercise, during intercurrent illness, or after correction doses are given. In addition to monitoring blood glucose concentrations, testing of the urine for ketones should be performed in the setting of chronic hyperglycemia or intercurrent illness. Families are instructed that the presence of urinary ketones indicates insulin deficiency, and supplemental doses of short- or rapid-acting insulin should be given frequently, along with fluids, until the ketones have “cleared.” In this way, the progression to more severe ketoacidosis may be prevented in most situations.
Nutritional Management Proper nutritional management is critical to the short- and long-term health of children with diabetes. Generally, terms such as “diet” should be avoided in favor of “meal plan,” both for the negative connotation associated with the former and for the simple fact that nutritional requirements for normal growth and development are the same in diabetic and non-diabetic children. However, adherence to meal plans and accurate assessment of carbohydrate intake are important for optimal glycemic control. The American Diabetes Association has adopted formal recommendations regarding general nutritional principles in diabetes, taking into account the short-term goals of blood glucose stabilization and the long-term goals of prevention/amelioration of macrovascular and microvascular complications of diabetes. The currently favored model of nutritional therapy is carbohydrate counting, based on the conceptual model of matching carbohydrate “doses” to insulin doses. As the carbohydrate content of foods has the greatest impact on blood glucose, the amount of carbohydrates ingested per meal or snack should be accurately assessed. Protein and fat intake, while important in the larger context of a healthy meal plan, are not counted to simplify the procedure. Recent changes in food labeling requirements have simplified the process, as most foods are clearly labeled with both the amount of carbohydrate grams per serving and the serving size. Foods less easily quantified may be weighed or estimated. Two popular approaches to regulating carbohydrate intake are (1) consistent carbohydrate servings per
15
meal/snack and (2) insulin-to-carbohydrate ratios. In the former, a standard amount of carbohydrates are eaten per meal or snack (e.g., 45 grams for breakfast, lunch, and dinner, and 30 grams each for midafternoon and bedtime snack). In this way, the insulin dose may be kept reasonably constant. In the latter, more flexible approach, there is no set intake. Rather, the child or parents decides upon the meal content, the carbohydrates are counted, and an insulin dose is calculated on the spot, based on a ratio of the number of insulin units per grams of carbohydrate. In younger children typical insulin to carbohydrate ratio is 1 unit: 15 gm, while an older child may require 1:10 and an insulin-resistant adolescent 1:5-7. Actual ratios of insulin to carbohydrates vary from child to child and may even vary in the same child from meal to meal or during periods of exercise. Long-term goals of nutritional management of diabetes include maintenance of nutrient intake balance of about 50% carbohydrate, 20% protein, and 30% fat (of which no more than 10% should be saturated). Most important, growth and weight gain should be monitored, and regular follow-up with a dietitian trained in diabetes management should be encouraged to individualize a meal plan for each child based on his or her needs and food preferences.
Exercise and Physical Fitness Establishment and maintenance of an active lifestyle should be a goal for all children, but they are especially important for children with diabetes. Exercise and increased physical fitness are associated with improved insulin sensitivity and glucose utilization, the clinical correlates of which are lower insulin requirements in general and, frequently, less pronounced blood glucose excursions after meals. Improvements in physical fitness are also frequently associated with greater self-esteem and motivation to participate in diabetes care. The effects of exercise must be carefully considered in the context of the entire diabetes care plan, because episodic exercise may predispose to acute hypoglycemia if the insulin dose is not reduced or extra carbohydrates are added proactively. Furthermore, intense physical activity in the setting of insulin deficiency (chronically poor diabetes control or recent omission of insulin) may provoke metabolic decompensation and DKA. Children participating in school sports or other programs should be counseled to monitor blood glucose before, during, and after exercise, because the hypoglycemic effects of exercise may be delayed and/or prolonged over the next 12 to 18 hours. We frequently recommend the reduction of dinner/bedtime NPH and, for pump users, decreases in basal rates to account for these exercise effects.
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Psychological Aspects There are few disorders in childhood that affect as many aspects of life as does diabetes. A previously healthy child must rely on multiple injections of insulin daily as well as lance the skin of the fingertips, draw blood, and test for glucose levels as many as 6 to 8 times a day. Flexibility and spontaneity in meal timing and content are frequently sacrificed. School and recreational activities are interrupted by the necessity of attending to testing or injecting. The practical problem of carrying insulin bottles, syringes, lancets, and glucose records to school, on dates, and on vacations is a constant reminder of the disease and that the child with diabetes is different in nearly every way. At any time, embarrassing or dangerous hypoglycemic reactions may occur, and there is the gnawing, ever-present knowledge of the chronic complications and morbidity that may develop even with good metabolic control. It is therefore imperative that the psychosocial functioning of the child and family is evaluated at diagnosis and periodically thereafter by the health care team, ideally a mental health professional. The diabetic child may be depressed, angry, or in denial of the severity of the disease. The parents may be feeling grief or guilt, especially if one of them has diabetes. Other siblings may be fearful of developing diabetes or jealous of the newfound attention that must be paid to the affected child. The additional stress of the diagnosis may sunder an already weakened family system to the point of divorce, violence, or neglect. Warning signs that require further psychosocial evaluation and intervention include declining school performance, isolation from friends and activities, new behavioral problems, and recurrent episodes of DKA. Frank depression and anorexia nervosa require referral to appropriate psychiatric services.
Medical Follow-up The importance of frequent follow-up by the diabetes health care team cannot be overemphasized. At each visit, the blood glucose logbooks should be reviewed and appropriate dosage or schedule changes should be instituted as needed. A detailed interim history should include questions relating to general health, energy, fatigue, polyuria or nocturia, intercurrent illnesses, hypoglycemic episodes, and the presence of abdominal symptoms such as pain, bloating, or diarrhea. It is important to remember the comorbidities of other autoimmune disorders that occur with an increased frequency in children with T1DM: thyroiditis, adrenal insufficiency, and celiac disease. The child should be weighed and measured at each visit, and pulse and blood pressure also documented. Physical examination of the child should focus not only on the general organ systems
but also on examination of the skin and insulin injection/pump insertion sites (for signs of lipohypertrophy or pigmentary changes), palpation of the thyroid, and determination of the sexual development stage. In older children or those with longer diabetes duration, examination should include the feet. A deceleration in growth, delay in sexual development, or finding of goiter may herald hypothyroidism, which occurs in approximately 5% of children with T1DM. The astute clinician should also consider that frequent, unexplained hypoglycemia or reduction in insulin requirements in the absence of exercise or activity may be a subtle indicator of hypothyroidism or adrenal insufficiency. Similarly, although the history of frequent, foul-smelling, greasy diarrhea are more obvious indicators of celiac disease, which occurs in about 2% of children with T1DM, the presence of abdominal pain, poor weight gain, and unexplained hypoglycemia may be the first and only signs. Measurement of HbA1c should be performed at each clinic visit. The HbA1c is an indirect indicator of the overall glycemic control based on the phenomenon that glucose binds in an irreversible, nonenzymatic manner to serum proteins at a rate proportional to the mean serum glucose concentration. The level of glycosylation of a given protein, therefore, depends on its exposure to glucose and its own rate of breakdown. For example, because the life span of the human red blood cell is about 90 to 120 days, measurement of glycosylated hemoglobin gives a measure of the mean glucose concentrations of the preceding 3 months. The most common measure of glycosylated hemoglobin is the HbA1c, and the conversion of the HbA1c to the mean blood glucose level may be estimated by the formula: Glucosemean (mg/dL) = [HbA1c (%) × 30] − 60
In children with decreased red cell survival time, however, such as occurs in sickle cell disease or spherocytosis, the HbA1c may be artificially low, because the time available for glycosylation is decreased. In these children, HbA1c measurements are not useful, and measurement of other glycosylated proteins, such as albumin, should be considered for analysis of long-term control. The availability of small, portable laboratory equipment that measures the HbA1c with a small sample of capillary blood in the clinic setting and offers results within minutes has greatly benefited the diabetes clinician. In this way, the HbA1c may be reviewed with the family at the clinic visit and compared with the logs. Discrepancies between the logs and the HbA1c may suggest improper testing technique or, more seriously, falsification of the data. In the case of the latter, deeper questioning into the family dynamics and psychosocial functioning of the child is warranted. Monitoring of the diabetic child for complications is an important function of the clinic visit, because many early
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Type 1 Diabetes Mellitus in Children
complications do respond to prompt intervention. Urinary albumin excretion may be measured in a spot sample by comparison with urinary creatinine; the urinary albumin/ creatinine ratio should be less than 30 mg albumin/1 g creatinine. Elevated spot samples should be confirmed by collections of first morning void or a timed overnight period to eliminate the confounding variable of benign orthostatic proteinuria. If the first morning void or timed overnight collection demonstrates microalbuminuria (>30 mg albumin/1 g creatinine, or >30 mg albumin excretion/24 hr), treatment with angiotensin-converting enzyme inhibitor or referral to pediatric nephrologist may be indicated. All diabetic children with hypertension, regardless of albumin excretion status, should be referred to a pediatric nephrologist for consideration of angiotensin-converting enzyme inhibitor therapy. Other screening studies for complications of diabetes includes measurement of serum lipid concentrations and referral for dilated retinal examination, both of which should be performed on a yearly basis in all pubertal children with diabetes or even in prepubertal children with diabetes duration of at least 5 years. Current guidelines suggest maintaining serum low-density lipoprotein concentrations below 100 mg/dL and serum triglycerides below 150 mg/dL in adults with diabetes, but there are no published recommendations specifically for children. Treatment for hypercholesterolemia and hyperlipidemia should include intensification of diabetes control and dietary interventions. There are little data on the efficacy and safety of specific lipid-lowering therapeutic agents in the pediatric population.
CONCLUSIONS The treatment of T1DM has evolved greatly since Leonard Thompson was given the first injection of insulin in 1921. In more than 80 years, T1DM has changed from a universally fatal disorder to an eminently manageable chronic condition, albeit one that requires a great deal of effort and expense to treat effectively. It is frequently said that insulin is not a cure for diabetes; the risk of long-term complications still looms large in the minds of diabetic patients and their loved ones. Efforts to prevent or reverse T1DM have historically been disappointing. Clinical trials of glucocorticoids, cyclosporin, nicotinamide, insulin, and other immunomodulatory agents have not been shown to significantly reduce the risk of diabetes in high-risk subjects. Pancreatic transplants are complicated surgical procedures, and the small number of viable donor specimens and the necessity of long-term immunosuppressive therapy have limited their general applicability.
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Recent developments have brought some new promise in the areas of diabetes prevention and islet cell replacement. Preliminary studies involving newer immunomodulatory agents have demonstrated improved survival of transplanted islet cells and reversal of clinical diabetes in experimental animals. The well-publicized Edmonton protocol demonstrated that a nonsurgical transplantation of donor islet cells into the liver followed by a glucocorticoidfree immunosuppressive regimen allowed seven people with T1DM to remain insulin free and in good metabolic control for more than 1 year. These studies are now being replicated in multiple centers in the United States. A simultaneous development in diabetes treatment has been the use of novel insulin delivery systems and glucose monitoring technologies. Clinical trials have shown inhaled insulin to be a potentially viable alternative to injection of rapid-acting insulin, and intraportal insulin delivery systems may hold some promise over current continuous subcutaneous insulin pumps. Minimally invasive blood glucose monitoring, using subcutaneous or transcutaneous sensors, at the present time function as adjuncts to routine finger-stick blood glucose monitoring and prototype systems in which these sensors communicate with insulin pumps in a “closedloop system” are under development. Whether the next revolution in diabetes management will be such “artificial β-cell” systems or true islet cell replacement, the goal of all diabetes clinicians at this time should be to optimize the metabolic control in their patients to maintain their health and their hope until such treatments become routine.
䉴
MAJOR POINTS
䉳
Diabetes is defined by the finding of an elevated blood glucose (BG); random BG greater than 200 mg/dL, fasting BG greater than 126 mg/dL, or, with an oral glucose tolerance test, 2-hour BG greater than 200 mg/dL. T1DM occurs in approximately 1 in 350 children under age 18 in the United States; about 15 new cases occur per 100,000 children per year. The gene or genes for T1DM are associated with the human leukocyte antigens of the major histocompatibility complex, located on chromosome 6. T1DM is caused by an autoimmune-mediated destruction of pancreatic β-cells in genetically susceptible individuals after a triggering event, usually a viral infection. At the present time, there is no available treatment to halt this autoimmune process and prevent the onset of T1DM. The classic symptoms of polyuria, polydipsia, and weight loss occur in the majority of children with T1DM.
Continued
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䉴
MAJOR POINTS—Cont’d
䉳
Diabetic ketoacidosis is defined as the presence of hyperglycemia (glucose >240 mg/dL), ketosis (positive serum or urinary ketones), and acidosis (pH < 7.30 and/or serum bicarbonate 85% for age and gender
High-risk ethnic group Family history of diabetes mellitus Sign or symptom associated with type 2 diabetes mellitus, including hyperlipidemia, hypertension, polycystic ovarian syndrome
Physical signs of puberty Or Age ≥10 years
Screen*
*Screening should be done every 2 years in the absence of symptoms. The preferred method of screening is a fasting plasma glucose test.
Table 2-1 Laboratory Tests at the Time of Initial Presentation Laboratory Test
Rationale and Commentary
Glucose related
Fasting glucose Oral glucose tolerance test Fasting plasma insulin C-peptide HbA1c
Lipids
Triglycerides Total cholesterol High-density lipoprotein cholesterol T4 (or free T4) Thyroid-stimulating hormone ALT, AST Total and direct bilirubin
An elevated glucose is required for diagnosis (see Box 2-1). The insulin and C-peptide levels are often elevated in type 2 diabetes mellitus (T2DM) and may be useful in the diagnosis of T2DM. For youth who are acidotic or who have experienced significant weight loss, these may be low secondary to “glucose toxicity.” An HbA1c that is normal does not rule out T2DM; however, an elevated HbA1c suggests persistent hyperglycemia and guides the choice of initial therapy. Hyperlipidemia is a common finding in individuals with T2DM and the leading cause of mortality. If the child is acutely ill, it is recommended that these studies be deferred until glycemic control is well established.
Thyroid Liver
Gonadal (pubertal females) Islet cell
Luteinizing hormone, follicle-stimulating hormone, androstenedione, dehydroepiandrosterone sulfate Anti–islet cell antibodies Anti-GAD65 antibodies
Kidney
Protein (microalbumin), blood urea nitrogen, creatinine
Specialty testing
24-Hour urinary free cortisol Insulin-like growth factor-I MODY genes
Hypothyroidism at the time of diagnosis is uncommon; however, this establishes a baseline. In adults, 5% to 10% with T2DM have nonalcoholic fatty liver disease (NAFLD). If the liver enzymes are elevated >3 times normal, this may affect the choice of medication. If persistently elevated, a liver biopsy or a search for other etiologies is recommended. Hyperandrogenism, hirsutism, dysmenorrhea, and polycystic ovarian syndrome are common in obese girls. Correction of these may occur with weight loss or reduction of hyperinsulinemia. If negative, these rule out type 1 diabetes mellitus (T1DM); however, 10% to 20% of adults with clinical picture of T2DM have positive antibodies. Positivity increases the likelihood that the patient requires insulin treatment. Lack of positivity is supportive of the diagnosis of T2DM (or other non-T1DM types of diabetes, such as maturity-onset diabetes of youth [MODY]). The true duration of diabetes in generally unknown in T2DM. These tests ensure that there is no evidence of overt dysfunction at diagnosis and establish a baseline. If protein is not found on urinalysis, then urine should be tested for microalbuminuria. Cushing syndrome should be considered in some cases (e.g., the child is short for age). Acromegaly must be considered if the youth has consistent clinical findings (prominent jaw, large hands and feet, etc.). These studies are not all commercially available. They may be of use in the evaluation of the atypical patient (e.g., the nonobese male who does not require insulin). The identification of a MODY variant has implications for treatment. Presently, the diagnosis of MODY is often made on clinical grounds.
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Type 2 Diabetes Mellitus in Children and Adolescents
MANAGEMENT OF TYPE 2 DIABETES MELLITUS General Principles Given the primary role of obesity and insulin resistance in the pathophysiology of T2DM, the major focus of management must be placed on those strategies that address these problems (e.g., reducing caloric intake, decreasing fat mass). Implementation of effective dietary and exercise strategies is of utmost priority, which as necessary should be supported by self-monitoring of blood glucose and medication. Before addressing treatment per se, it is essential to consider the treatment environment and how it differs between T1DM and T2DM. This environment includes the health care system, the social milieu, cultural attitudes, family dynamics, economic trends, and political climate. Most currently practicing pediatricians had some exposure to T1DM in children during their training; can access general pediatric textbooks detailing the pathophysiology, diagnosis, and treatment of T1DM; and can consult competent pediatric endocrinologists in their communities. In contrast, few active pediatricians had any exposure to T2DM in children during their training, there is minimal information on T2DM in general pediatrics, and only a limited number of pediatric endocrinologists have experience with T2DM. Many of the medications used to treat T2DM and its comorbidities are not yet tested or approved for use in the pediatric population, so there is minimal literature on any unique benefits or problems related to their use in children. Some studies that address these issues are under way or in the planning phase. As in many chronic disease models, family structure, culture, and belief systems have a significant impact on how the family perceives and manages T2DM in youth. In contrast to T1DM, almost all children with T2DM are adolescents: most are in middle school or high school. Although the implications specific to T2DM have not been explored, there are well-documented developmental and social differences that occur with the onset of adolescence. Children newly diagnosed with T1DM are often significantly symptomatic at diagnosis, 40% to 80% may be hospitalized, and as many as half of those require intensive care. On the other hand, few children with T2DM have severe symptoms at diagnosis, and even fewer require hospitalization or intensive care. Most families of children with T1DM have little or no experience with diabetes, whereas most families of children with T2DM have one or more family members already affected by the disease. In the former case, diabetes is unfamiliar and frightening, whereas in the latter case, diabetes is familiar and the only threat is perceived to be in the far future, if at all. Furthermore, in the case of T2DM, not
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only is diabetes familiar but also the affected family members often have been unsuccessful in adequately managing their diabetes. Access to health care may be more limited for children with T2DM: it is well documented that minority communities have less access to care due to both geographic (e.g., fewer neighborhood health care providers) and economic (e.g., fewer children with health insurance) issues. Eating behaviors, food preferences, and food choices are largely established in early childhood and are often limited by parental experience, background, and income. Families in which multiple caretakers work to support the family may have limited time to prepare healthful, lower-calorie meals, opting instead for less-nutritious, higher-fat “fast” foods. Even if efforts are made to prepare food at home, supermarkets may be less accessible to economically challenged families, who then purchase their groceries at corner convenience stores, where fresh fruits and vegetables may be more expensive, of lower quality, and less available. There is a common perception that obesity is a significant source of social distress or discomfort to adolescents. This may be true is some communities but is by no means true in all communities. In schools where 45% of the children are overweight or obese, there may be no adverse social consequences (e.g., teasing) related to being overweight. In fact, there may be some advantages to being overweight, because the youth with T2DM often is taller than average and more sexually mature. Even for motivated, educated, middle-class adults, weight control or weight loss is difficult. As a consequence, weekly meetings or weekly visits are a routine part of most of popular weight loss programs. In the successful pediatric obesity programs, the initial intervention requires weekly interactions for several weeks, followed by biweekly or monthly reinforcement for an additional time period. It is unrealistic to think that effective strategies for weight loss, or related behaviors, that are crucial to T2DM management can be instituted and sustained with the quarterly visit to the diabetes clinic that has been standard for T1DM care. Therefore, a key element of T2DM care is frequent contact. Other components of management include family involvement, school participation, and health care team familiarity with the individual child, as well as the child’s family, neighborhood, and school. Clarity and simplicity are the key concepts in managing adolescents and children with T2DM. Youth, like adults, have competing priorities that often interfere with diabetes management. Furthermore, the capacity of youth for longterm planning is limited. Within this context, it is crucial that the diabetes care team understands the individual youth’s priorities and attempts to match those priorities with those of diabetes care—a task that is made more difficult by the reticence of many teenagers to talk openly to any
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adult. It is imperative to sharply limit the goals of any particular interaction and to provide education consistent with the adolescent’s life experience and education.
Medical Nutrition Therapy The goals of medical nutrition therapy are to normalize serum glucose and lipid levels, achieve weight loss or stabilization, and develop healthy and sustainable eating habits. There are no dietary guidelines specific to children and adolescents with T2DM. Until such guidelines are developed, the ADA guidelines for adults with T2DM should be adequate and appropriate, as summarized in Box 2-3. The safety and efficacy of alternative approaches to dietary restrictions and modifications (high fat, low fat, high protein, low carbohydrate) in children with obesity, insulin resistance, or T2DM have not been established. Although carbohydrate counting is now widely used for children with T1DM, it is not always a wise choice for the adolescent with T2DM because there is a greater need to be attentive to the total caloric content as well as to the amount and composition of the fats. From a practical point of view, some of the more complex concepts such as “calorie” and “ratio and proportion” are beyond the educational level of many children and parents. Greater benefit may be achieved by focusing on eating behaviors rather than on food choice and caloric content per se. Finally, concern has been expressed regarding encouraging weight loss in children and possible dire consequences on adult height and psyche. However, weight stabilization or modest supervised weight loss in overweight children is safe; therefore, it is reasonable to assume that the same is true with regard to weight loss in children with T2DM. Educational efforts must be targeted at all individuals who make choices about the child’s meals: the adolescent, parents, grandparents, school cafeteria personnel, and afterschool program personnel. In general, the initial focus is on the person who is most responsible for the youth’s intake. For the younger adolescent with T2DM, this is often the
Box 2-3 Nutrient Intake and Distribution NUTRIENT
DISTRIBUTION
Protein Total fat Saturated fat Polyunsaturated fat Carbohydrate Fiber Sodium
10-20% of total calories 4 ml) or pubic hair is not present by 14 years of age. Puberty is also considered abnormal if it progresses at a slow pace after starting at an appropriate age. The mean duration from the onset of puberty to menarche is 2.4 ± 1.1 years, and from onset to achievement of adult testicular volume, 3.2 ± 1.8 years. An unusually slow progression or “stalled or arrested” pubertal maturation merits comprehensive assessment to exclude pathology. In girls, it is important to determine whether the signs of puberty are completely absent or incomplete with discordance in pubic hair and breast development. Individuals with androgen insensitivity syndrome, for example, may have well-developed breasts with absent or scant pubic and axillary hair.
DIFFERENTIAL DIAGNOSIS Delayed puberty can be caused by deficient hypothalamic and/or pituitary function (low gonadotropins and low sex 87
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Box 6-1
Causes of Pubertal Delay
HYPOGONADOTROPIC HYPOGONADISM Constitutional delay in growth and development Idiopathic hypogonadotropic hypogonadism Kallmann syndrome (KAL-1 gene mutations) Adrenal hypoplasia congenita (DAX-1 gene mutations) Mutations in the genes for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and the gonadotropin-releasing hormone (GnRH) receptor Mutations in prohormone convertase, homeobox, and PROP-1 genes Structural Septo-optic dysplasia Hypothalamic and pituitary tumors Head trauma, radiation, surgery Central nervous system infections, infiltrative diseases Prader-Willi and Lawrence-Moon-Biedl syndromes Lifestyle and body composition: undernutrition, anorexia nervosa, intense exercise Chronic diseases: inflammatory bowel disease, hepatic and renal diseases, malignancies, iron overload HYPERGONADOTROPIC HYPOGONADISM Males Klinefelter syndrome Gonadal dysgenesis Testicular regression syndrome Bilateral orchitis, testicular surgery, radiation, chemotherapy Abnormalities in testosterone synthesis 5α-Reductase deficiency Inactivating mutations of LH and FSH receptor genes Androgen-insensitivity syndromes Noonan syndrome Females Turner syndrome, gonadal dysgenesis (complete or partial) Idiopathic primary or premature ovarian failure Surgical oophorectomy, radiation, or chemotherapy Inactivating mutations of LH and FSH receptor genes Androgen insensitivity EUGONADAL CAUSES Partial or complete noncanalization of the vagina, imperforate hymen
steroids) or primary gonadal failure (high gonadotropins and low sex steroids). Differential diagnosis of the former includes benign variants of normal and many secondary causes of hypogonadism, whereas the latter always indicates gonadal pathology (Box 6-1). Normal endocrine function in conjunction with anatomic anomalies that hinder menstrual flow comprise the third category. 1. Hypogonadotropic hypogonadism (low luteinizing hormone [LH] and follicle-stimulating hormone
[FSH]): hypothalamic-pituitary dysfunction or immature gonadal axis 2. Hypergonadotropic hypogonadism (high FSH and LH values): primary gonadal failure 3. Eugonadism (normal FSH and LH values): primary amenorrhea secondary to uterine, cervical, or vaginal structural defects
Hypogonadotropic Hypogonadism Hypogonadotropic hypogonadism encompasses miscellaneous conditions ranging from a familial pattern of constitutional delay to central nervous system lesions impairing hypothalamic or pituitary function. This category includes genetic defects in gonadotroph differentiation or pituitary development and all secondary causes of central hypogonadism such as systemic illness, undernutrition, psychosocial stress, trauma, or infiltrative diseases. By far the most common diagnosis in this category is constitutional delay in growth and development. Constitutional Delay in Growth and Development
An exaggerated delay of pubertal onset in an otherwise healthy child is a common variant of normal in which the physical and biochemical markers of puberty resemble those of a younger child. Puberty occurs spontaneously but at a later age with a concomitant delay in the pubertal growth spurt. A family history of delayed puberty is usually elicited. Many more males than females seek medical attention with this diagnosis in comparison with other causes of hypogonadism. Children with constitutional delay exhibit a decline in growth velocity at ages 2 to 3 years with crossing of height percentiles and delay in skeletal maturation. Growth subsequently proceeds at a low normal rate and bone age remains delayed for age until the pubertal growth spurt. Pubertal staging and stature are commensurate with bone age rather than chronological age. At the usual age of puberty, the short stature (often 2-3 SDs below the mean for age) of these children becomes more noticeable as they maintain a prepubertal growth rate while their peers enter puberty and have accelerated growth. Final height is achieved late and is often in the low-normal range but consistent with genetic potential. Although constitutional delay is considered a benign condition, decreased bone mineral density in young adult men with a history of constitutional delay has been reported. Before making a diagnosis of constitutional delay, systemic illnesses and other causes of hypogonadism should be excluded with a comprehensive history and review of systems and a thorough physical examination. Constitutional delay in puberty can be difficult to distinguish from isolated hypogonadotropic hypogonadism, often requiring longterm monitoring to determine if puberty occurs sponta-
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Delayed Puberty
neously. Although not definitive, assessment of adrenarche can be helpful because children with constitutional delay generally have a later adrenarche and lower values of dehydroepiandrosterone sulfate (DHEAS) than do those with hypogonadotropic hypogonadism. Early morning testosterone values are an early marker of impending pubertal changes; 100% of boys with a value greater than 0.7 nmol/L (20 ng/dL) manifest signs of puberty within 15 months. Gonadotropin determination has been less useful. Neither basal nor gonadotropin-releasing hormone (GnRH)-stimulated FSH and LH values discriminate between these two conditions. Reports of differential responses to potent GnRH agonists or to successive doses of GnRH offer promise for development as diagnostic tests. Idiopathic Hypogonadotropic Hypogonadism
Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome are isolated defects in GnRH secretion with no other hormonal deficits and no structural lesions of the hypothalamus or pituitary. Individuals with either of these conditions have complete or partial absence of LH pulses that can be restored with pulsatile administration of GnRH, indicating that the defect is at the hypothalamic level. Children with IHH have sexual infantilism and delayed skeletal maturation. Males have eunuchoid body proportions (upper-to-lower segment ratio of 6-cm difference between arm span and standing height), a high pitched voice, and prepubertal testes. Females have no breast development and primary amenorrhea. Gonadotropin deficiency is occasionally diagnosed in newborn infants with cryptorchidism and microphallus because LH-stimulated testosterone secretion during late gestation is required for complete testicular descent and phallic growth. Hypogonadotropic hypogonadism can also present as slowly progressive or arrested puberty, decreased libido, impotence and oligospermia or azoospermia in men, and secondary amenorrhea and infertility in women. The majority of patients with isolated gonadotropin deficiency and complete sexual infantilism lack LH pulses, a surrogate marker for GnRH pulse generator activity. A milder phenotype is observed with the developmental arrest pattern of gonadotropin secretion. These individuals have the sleep entrained pattern of early puberty, with predominantly nighttime pulses. Puberty can be stalled after onset or progress to spermatogenesis without full virilization, as seen with the fertile eunuch syndrome. IHH can be sporadic (66%) or familial (34%), and several gene mutations have been identified in both forms (Table 6-1). Among a series of 106 patients seen at Massachusetts General Hospital, inheritance was X-linked in 11%, autosomal dominant in 64%, and autosomal recessive in 25%. The degree of hypogonadism and the LH pulse
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profile can both vary within the same pedigree. GnRH receptor mutations can cause disordered LH pulse frequency or amplitude, or the LH can be bioinactive. Kallmann Syndrome
Kallmann syndrome, IHH and anosmia or hyposmia, is the most common form of isolated gonadotropin deficiency (1 in 10,000 males and 1 in 50,000 females). Most cases are sporadic, and of these, less than 5% have mutations in the KAL gene (Xp22.3) encoding anosmin-1. Of the familial forms, X-linked recessive (KAL-1) is the most common, followed by autosomal dominant (KAL-2) and then autosomal recessive (KAL-3). Half of families with X-linked inheritance have deletions or point mutations of the KAL gene. Anosmin-1 is a neural cell adhesion protein that provides a scaffold for GnRH neurons and olfactory nerves during their embryonic migration from the olfactory placode to the medial basal hypothalamus and olfactory bulb, respectively. Consequently, olfactory bulbs are absent or structurally abnormal on magnetic resonance imaging in the majority of patients with Kallmann syndrome. The embryonic expression of the KAL gene explains other associated clinical findings such as synkinesia (i.e., mirror movements of the hands; corticospinal tract involvement), abnormal eye movements (oculomotor nucleus), visual defects (retina), nystagmus and ataxia (cerebellum), midfacial clefts (midfacial mesenchyme), and renal agenesis (mesonephros and metanephros) (Figure 6-1). Unilateral renal agenesis has been described in 50% of boys with KAL gene mutations. Other manifestations include gynecomastia, short metacarpals, pes cavus, sensorineural defects, and epilepsy. As with other forms of hypogonadotropic hypogonadism, Kallmann syndrome can also present at birth with microphallus and cryptorchidism. Members of a family with the same KAL mutation have phenotypic variability suggesting some compensation by redundant proteins. Carrier females may have hyposmia, delayed menarche, or irregular menses but are usually fertile. DAX-1 Gene Mutations
Mutations of the DAX-1 gene located in the DSS (dosagesensitive sex reversal) region at Xp21 cause hypogonadotropic hypogonadism at puberty in conjunction with early-onset adrenal insufficiency (X-linked adrenal hypoplasia congenita). DAX-1 is an orphan nuclear receptor that is essential for development of the adrenal cortex and regulation of gonadotropin secretion at both the hypothalamic and pituitary levels. In most cases, the hypothalamicpituitary dysfunction is not evident until puberty. Similar gonadotropin deficiencies have been described in a woman with homozygous DAX-1 mutations, whereas female carriers are reported to have delayed puberty. A contiguous gene
Xp22.3 Xp21 9q33
7q31.3 1p31 3p21.1-21.2 9q34
5q
4q21.2 19q13.3 11p13
KAL DAX-1 SF1
Leptin Leptin receptor HESX1 LHX3
PROP1
GnRHR LHb FSHb
HH, anosmia Congenital adrenal hypoplasia, HH XY sex reversal with müllerian structures, adrenal failure Obesity, HH Obesity, HH Septo-optic dysplasia, panhypopituitarism Short stature, hypothyroidism, HH, hypoprolactinemia, cervical spine rigidity Short stature, hypothyroidism, HH, hypoprolactinemia HH Isolated LH deficiency Isolated FSH deficiency
Phenotype
N/↓ N/↓ ↓ ↑
N/↓ N/↓ N/↑ ↓
↓
↓
Pituitary Pituitary Pituitary Pituitary Pituitary
N/↓ N/↓ ↓
↓ N/↓ N/↓
↓ N/↓ N/↓ N/↓ N/↓ ↓
FSH
LH
Hypothalamus Hypothalamus Pituitary
Hypothalamus Hypothalamus, pituitary Hypothalamus, pituitary
Location of Central Nervous System Defect
Autosomal recessive Autosomal recessive Autosomal recessive Autosomal recessive
Autosomal recessive
Autosomal recessive Autosomal recessive Autosomal recessive
X-linked recessive X-linked recessive Autosomal recessive?
Inheritance
CNS, central nervous system; GnRHR, gonadotropin-releasing hormone receptor; LH, luteinizing hormone; FSH, follicle-stimulating hormone. Adapted from Layman LC: Genetics of human hypogonadotropic hypogonadism, Am J Med Genet 1999;89:242; and Ackermann JC, Weiss J, Lee EJ, et al: Inherited disorders of the gonadotropin hormones, Mol Cell Endocrinol 2001;179:89, with permission.
Gene Locus
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Table 6-1 Gene Mutations Causing Hypogonadotropic Hypogonadism (HH)*
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Figure 6-1 Correlation between the sites of KAL gene expression in human and chick with the observed clinical phenotype of Kallmann syndrome. (Reprinted from Layman LC. Genetics of human hypogonadotropic hypogonadism, Am J Med Genet 1999;89:242, with permission.)
deletion on Xp21 can lead to an association of this disorder with Duchenne muscular dystrophy and glycerol kinase deficiency. As with KAL-1, genotype-phenotype correlations have been poor even within families, suggesting compensation by modifier genes. DAX-1 also plays a role in ovarian formation; thus, duplication of this gene causes sex reversal in genetic males. Gonadotropin-Releasing Hormone Receptor Mutations
GnRH binds to a G protein–coupled receptor (4q13.1) that signals through the phosphoinositol pathway to increase intracellular calcium and stimulate gonadotropin synthesis and secretion. Mutations in the GnRH receptor gene have been identified in one third of familial cases of hypogonadotropic hypogonadism without anosmia and in 2% to 7% of patients with IHH (Figure 6-2). These mutations compromise GnRH action to varying extents by interfering with ligand binding or decreasing phospholipase C activation and phosphoinositol
Figure 6-2
Structure of the gonadotropin-releasing hormone receptor and location of inactivating mutations. Each star represents a mutation identified in an independent family (with one or more affected patients). (Reprinted from de Roux N, Milgrom E: Inherited disorders of GnRH and gonadotropin receptors, Mol Cell Endocrinol 2001;179:84, with permission.)
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production. For example, Tyr284Cys and Ala129Asp cause complete hypogonadotropic hypogonadism, whereas Gln106Arg, Ser217Arg, and Arg262Gln are partial defects. Thus far, no mutations of the GnRH gene have been found in patients with hypogonadotropic hypogonadism. Males with mutations of the GnRH receptor are hypogonadal with small, sometimes undescended testes. Females have poor breast development and amenorrhea. Gonadotropins and sex steroid levels are low. Despite the receptor defect, 75% exhibit a rise in LH and FSH with a single intravenous dose of GnRH (100 μg), whereas 50% require pulsatile administration of GnRH. Thus, a mutation in the GnRH receptor does not necessarily preclude therapy with pulsatile GnRH. Miscellaneous Single-Gene Defects
Prohormone convertase (5q15-q21) mutations disrupt GnRH processing to cause hypogonadotropic hypogonadism and impair processing of insulin and pro-opiomelanocortin to cause obesity. Inheritance is autosomal recessive, and only a single case has been reported so far. A defect in the leptin gene (Arg105Trp; 7q31.3) causes extreme obesity, hyperinsulinemia, and hypogonadotropic hypogonadism. The pubertal delay can be treated with exogenous GnRH, gonadotropins, or sex steroids. Unlike the leptin-deficient ob/ob mice, human leptin deficiency does not cause stunted growth, hyperglycemia, or hypercortisolemia. Defects in the leptin receptor gene (1p31) manifest a similar phenotype, but leptin is elevated. Mutations in PROP-1 (5q), a pituitary transcription factor, cause autosomal recessive deficiency of growth hormone, thyrotropin, prolactin, FSH, and LH. The pituitary fails to respond to growth hormone releasing hormone (GHRH), thyrotropin releasing hormone (TRH), or GnRH. Males have small genitalia, delayed or incomplete secondary sexual maturation with infertility, and growth failure. A 2-bp deletion (301-302delAG) accounts for 55% of familial and 12% of sporadic cases of combined pituitary hormone deficiency, but many other missense mutations and deletions have been identified. The onset and severity of pituitary dysfunction vary widely within the same genotype. Midline defects such as septo-optic dysplasia or absence of the corpus callosum may be associated with pituitary gland hypoplasia. In septo-optic dysplasia, abnormal development of the prosencephalon leads to optic nerve involvement (pale optic discs with pendular nystagmus and even blindness) and hypothalamic defects, including growth hormone deficiency, diabetes insipidus, hypocortisolism, hypothyroidism, and hypogonadotropic hypogonadism. An Arg53Cys missense mutation in HESX, a homeobox gene that affects DNA binding, has been identified in a family of affected individuals with septo-optic dysplasia.
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Hypothalamic and Pituitary Tumors
Craniopharyngiomas, the most common tumor causing hypopituitarism in childhood, account for 6% of all brain tumors in children and for 80% to 90% of tumors arising in the pituitary region. The peak incidence is between 5 and 14 years of age. Although the initial symptoms are usually neurological, namely headaches (13%) and visual disturbances (35%), endocrine dysfunction is already present in 70% to 80% of all patients at diagnosis. Up to 75% of patients have growth failure and growth hormone deficiency, 40% have gonadotropin deficiency, and 25% have ACTH and TSH deficiency. Postoperatively, panhypopituitarism, including diabetes insipidus, is common. Cushing disease and pituitary adenomas are rare causes of hypogonadism in children. Head trauma, central nervous system radiation, surgery, infections, and infiltrative disorders can disrupt hypothalamic or pituitary function and cause hypogonadotropic hypogonadism. Genetic Syndromes
Hypogonadotropic hypogonadism is common in PraderWilli syndrome. Other features include muscular hypotonia, mental retardation, short stature, obesity, and small hands and feet. Prader-Willi syndrome is caused by loss of function of the paternal allele for imprinted genes such as SNRPN, a spliceosomal protein, and SNURF, a gene that regulates imprinting because of deletions or maternal uniparental disomy of chromosome 15q11-q13. Noonan syndrome is a relatively common disorder (1:1000-2500) characterized by delayed puberty, proportionate short stature, valvular pulmonic stenosis and/or hypertrophic cardiomyopathy (68%), cryptorchidism (60%), nuchal webbing with a low hairline, and chest deformities. The characteristic facial features include hypertelorism, down-slanting palpebral fissures, malrotated lowset ears, high arched palate, and micrognathia. The phenotype can include mild developmental delay and mental retardation, learning disabilities, language delay, and hearing loss. Puberty generally occurs spontaneously, although primary gonadal failure may also occur secondary to bilateral cryptorchidism. Noonan syndrome can be autosomal dominant or recessive in inheritance, or sporadic. Miscellaneous mutations in protein tyrosine phosphatase, nonreceptor type II, PTPN11 (chromosome 12q24.1), have been identified in one third to one half of patients who have undergone molecular analysis. Bardet-Biedl syndrome is characterized by mental retardation, pigmentary retinopathy, polydactyly, obesity, and hypogonadism. Females with this syndrome have both hypogonadotropic hypogonadism and primary gonadal failure. The genetic basis is unknown.
Autosomal recessive syndromes such as multiple lentigines and Carpenter syndrome are also associated with hypogonadotropic hypogonadism. Lifestyle and Body Composition Changes
Intense Exercise (Female Athletic Triad) The female athletic triad of primary or secondary amenorrhea, disordered eating, and osteoporosis illustrates the potential deleterious effects of intensive exercise training on the HPG axis. A progressive increase in the intensity of exercise leads to menstrual irregularity due to luteal-phase defects, then oligomenorrhea and anovulation, and finally amenorrhea. The hormonal correlates of this are an initial decrease in frequency of LH pulses followed by more severe disorders of pulsatility, and then complete functional arrest of the HPG axis. The incidence of hypogonadism and menstrual dysfunction depends on nutritional status and the type, intensity, and duration of exercise. Up to 50% of ballet dancers and high-intensity runners, as opposed to 12% of swimmers, become amenorrheic. The body fat hypothesis of Frisch and McArthur attributes this difference to the lower percentage of body fat in runners and ballet dancers (=∼15%) compared with that in swimmers (=∼15%). On the other hand, when ballet dancers interrupt their training, menses often return without altering the lean body–to–fat mass ratio, suggesting that exercise may have an independent role. Currently, low energy availability rather than change in body fat composition or the stress of exercise is believed to be the critical factor. When the availability of metabolic fuel falls below a critical level due to decreased intake and/or increased energy expenditure, the HPG axis is downregulated, a mechanism similar to that caused by eating disorders. This can be avoided by increasing intake to compensate for the increased energy expenditure. The second component of the female athletic triad, disordered eating, has been reported in up to 32% of college age athletes and begins at an average age of 14 years. Disordered eating habits, such as binging, self-induced vomiting, and laxative and diuretic abuse, are regarded by many athletes as ∼15%) harmless. The prevalence is highest among gymnasts (= ∼15%). and long distance runners and field hockey players (= Despite comparable total caloric intake, athletes with this syndrome consume 50% less fat and more carbohydrate and fiber than their menstruating counterparts. Osteoporosis, the third component of the triad, is a serious complication of exercise-induced hypogonadism and amenorrhea. Although weight-bearing exercise can improve bone mineral density, exercise that is intense enough to cause amenorrhea leads to bone loss, even at weight-bearing sites, and increased risk of stress- and running-related fractures. Consequently, amenorrheic athletes have a lower
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lumbar bone mineral density than do eumenorrheic athletes matched for sport, age, weight, height, and training schedule. In boys and men undergoing endurance exercise training, the hypothalamic-pituitary-testicular axis is perturbed to the extent of reducing testosterone concentrations, but puberty is rarely delayed or arrested. Although the longterm consequences of reduced testosterone concentrations in athletes are unknown, its effects in other androgen-deficient states indicate that spermatogenesis and bone mineralization may be compromised. Undernutrition and Anorexia Nervosa Food restriction and weight loss are well-known causes of menstrual disorders. Reduced energy availability from caloric restriction alters LH pulsatility to a greater extent than that seen with the female athletic triad. In healthy cycling women, moderate degrees of food restriction lead to low estradiol levels and anovulation despite normal LH levels. After 2.5 weeks of severe starvation, LH pulsations revert to a prepubertal pattern. A 10% to 15% loss of body weight (corresponding to a 30% loss in body fat) can delay puberty or cause menstrual irregularities and amenorrhea. The hypogonadism leads to a 20% to 68% prevalence of osteoporosis in different studies. Decreased insulin-like growth factor-I levels, GH resistance, and hypercortisolism potentiate the effect of hypogonadism and nutritional deficiencies on bone loss. Moreover, osteopenia due to anorexia nervosa is more severe in adolescents than in adults, even when the duration of amenorrhea is comparable. Adolescence is a period of rapid bone mass accumulation, with 90% of peak bone mass achieved by the age of 18 years. This active bone mass accrual is significantly reduced with adolescent anorexia nervosa and cannot fully “catch up” with weight recovery. Systemic Illnesses Any major systemic illness, particularly inflammatory bowel disease, malignancies, and chronic infections, can cause pubertal delay and poor growth. Poor nutrition, chronic illness, pain, and psychosocial factors can all disrupt the HPG axis. Chronic iron overload secondary to multiple transfusions in children with severe thalassemia or hemochromatosis causes pituitary damage and hypogonadotropic hypogonadism. Anterior pituitary involvement is selective, with gonadotropes and lactotropes being affected earlier than other pituitary cells. Boys with thalassemia have low nocturnal gonadotropins and a poor LH response to GnRH. Their testosterone response to human chorionic gonadotropin (hCG) is lower than that of boys with constitutional delay, implying that there is also damage to the testes.
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Hypogonadism associated with human immunodeficiency virus infections can cause both primary and secondary hypogonadism. Weight loss and severe illness lead to hypogonadotropic hypogonadism, whereas direct involvement of the gonads by the virus, opportunistic infections, or associated malignancy causes primary gonadal failure. Severe immune dysfunction is also associated with significant delays in pubertal development.
Hypergonadotropic Hypogonadism
Males Klinefelter Syndrome
Klinefelter syndrome, a common cause of primary hypogonadism (1 in 600 males), is characterized by testicular failure, androgen deficiency, and impaired spermatogenesis. The karyotype is 47,XXY in two thirds of patients and mosaic (46,XY/47,XXY) or a variant (48,XXXY, 49,XXXXY) in the remaining third. The extra X chromosome is acquired through nondysjunction during parental gametogenesis or a mitotic error in the zygote. Paternal nondysjunction accounts for 53% cases of Klinefelter syndrome, maternal meiotic errors for 43%, and postzygotic errors for 3%. The incidence of maternal meiotic I errors increases with increasing maternal age. Pathogenesis Testosterone values in cord blood of neonates with Klinefelter syndrome are usually lower than those of nonaffected infants, and germ cells are already reduced in number during infancy. During childhood, LH, FSH, testosterone, and the testosterone response to GnRH are all in the normal prepubertal range. At puberty, however, LH, FSH, and sex hormone–binding globulin (SHBG) become elevated, whereas testosterone is low or low-normal and free testosterone and inhibin are low. The testes become small and firm and develop the classic features of hyalinization and fibrosis of the seminiferous tubules and oligospermia with eventual azoospermia. Spontaneous fertility, however, has been reported in men with 46,XY/47,XXY mosaicism. Clinical Features Although testicular atrophy and hyalinization of the seminiferous tubules appear to be invariant features of Klinefelter syndrome in adults, the timing of testicular failure and the variability of associated features are related to the degree of mosaicism. Prepubertal testicular failure is rare but causes pubertal delay and results in eunuchoid body proportions, with arm span greater than height by 2 cm or more, long legs, and tall stature. The genitalia are usually
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normally formed, but the phallus may be small in size. Facial, axillary, and pubic hair are sparse and body habitus is more feminine with decreased muscle mass and a feminine fat distribution. Gynecomastia is common and differs from that of most high-estrogen states in having interductal rather than ductal hyperplasia. Leydig cell failure after the onset of puberty has milder manifestations, with more extensive pubic and facial hair and varying degrees of gynecomastia. Despite a normal onset of puberty, an eunuchoid habitus with long lower extremities causing disproportionate tall stature is common and postulated to be caused by duplication of genes modulating growth on the extra X chromosome. The phallus is normally virilized, although the testes are small, often less than 4 mL in volume. Infertility, small testes, and elevated gonadotropin levels are common (90-100% of patients). Other findings include low testosterone values (65-85% of patients), decreased facial and pubic hair (30-80%), gynecomastia (50-75%), and a small phallus (10-25%). The hypogonadism can lead to significant osteopenia and osteoporosis, which are alleviated by timely implementation of testosterone replacement. Delayed puberty is the more common manifestation of Klinefelter syndrome, but precocious puberty has been reported and occurs 5.5 times more frequently than expected. Precocious puberty may be idiopathic or secondary to hypothalamic hamartomas and gonadal or extragonadal germ cell tumors. Associated Disorders Men with Klinefelter syndrome have an increased incidence of mild adult-onset diabetes mellitus, autoimmune disorders such as Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, deep venous thrombosis, pulmonary embolism, and venous ulcers. Thinning of the dental enamel from enlargement of the pulp cavity causes problems with dental decay. The low testosterone levels and reduced numbers of lymphocytes and suppressor T cells may contribute to the propensity for autoimmune disease. Testosterone replacement has been reported to ameliorate clinical symptoms and improve immune function. Breast cancer is increased by 20-fold in men with Klinefelter syndrome with estimated incidences of 0.9% to 3%. Gynecomastia is a predisposing factor, although the increased risk is not considered high enough to support prophylactic mastectomy. Extragonadal germ cell tumors are also more common in Klinefelter syndrome, possibly due to persistently elevated gonadotropin levels. The possibility of an underlying increased risk for malignancy is supported by the report of an abnormally high transformation frequency by simian virus 40 (SV40) of fibroblasts from 47,XXY patients.
Individuals with Klinefelter syndrome may have neuropsychological impairment and behavioral problems. During childhood, speech and language development and the acquisition of motor milestones, strength, and coordination can be delayed. Although full-scale IQs are similar to controls and siblings, academic difficulties are common due to verbal processing deficits, diminished short-term memory, poor data retrieval skills, and an increased incidence of attention deficit disorder. Emotional immaturity, poor selfesteem, social stress and anxiety, apathy, and poor impulse control lead to underachievement at school. Individuals with more than one extra X chromosome have greater intellectual impairment. Anxiety, neuroses, psychoses, and depression are not unusual in such adults. Testosterone replacement is reported to improve psychological wellbeing and social functioning. Management Klinefelter syndrome is usually diagnosed at puberty when pubertal delay, eunuchoid proportions, and small testes lead to evaluation and subsequent diagnosis. Occasionally, the diagnosis is made by prenatal amniocentesis or because of behavioral or school performance problems. Testosterone treatment is started at the time of diagnosis or at puberty if the diagnosis is recognized early, and treatment should be continued throughout life. Replacement of testosterone allows normal development of pubertal characteristics and a masculine body habitus, prevents osteopenia and osteoporosis, increases the numbers of lymphocytes (specifically suppressor T cells), and improves self-esteem and behavior. Individuals with Klinefelter syndrome can produce sperm with no cytogenetic abnormalities and have fathered children with normal sex chromosomes. In 20% of men with Klinefelter syndrome, primarily those with a mosaic karyotype, germ cells can be recovered from testicular biopsy samples for selection of viable spermatogonia and cryopreservation. Some spermatozoa carry an extra X chromosome, suggesting the need for further selection of sperm from biopsy specimens to avoid transmission of this syndrome by assisted reproduction techniques. In vitro fertilization by intracytoplasmic injection of sperm has successfully produced nonaffected infants. Mutations in Gonadotropin Genes and Receptors
An LHb gene mutation has been identified in a 17-year-old boy with pubertal delay, small testes, and normal male genitalia. LH was elevated, whereas FSH and testosterone were low and testicular biopsy revealed spermatogenic arrest with complete absence of Leydig cells. Molecular analysis identified a homozygous Gln54Arg point mutation in exon 3 that impaired binding to the LH receptor, making the LH biologically inactive. Although postnatal Leydig cells were
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absent, the external genitalia were virilized, confirming that fetal Leydig cell development and testosterone synthesis are not dependent on fetal LH secretion. The LH receptor (chromosome 2p21) is a G protein– coupled receptor with seven transmembrane domains. LH binding activates adenylate cyclase and, at high concentrations, phospholipase C to stimulate Leydig cell development and regulate testosterone synthesis. The phenotype of 46,XY individuals with LH receptor mutations varies according to the severity of the mutation. Milder defects cause a reduction in Leydig cell number and present as delayed puberty with normal or undervirilized genitalia. The wölffian ducts may be incompletely developed and testes may or may not be descended. Absence of the receptor with complete unresponsiveness to either LH or hCG causes XY sex reversal. The external genitalia are female, both müllerian and wölffian structures are absent, and intraabdominal testes are present but lack Leydig cells. Males with mutations of the genes for FSHb or its receptor do not have delayed puberty. Spermatogenesis may be impaired, but the development of secondary sexual characteristics proceeds normally because LH signaling is unaffected. Miscellaneous Causes of Testicular Dysfunction
Testicular injury from irradiation or gonadotoxic chemotherapy causes gonadal dysfunction in cancer patients and those undergoing radiation for bone marrow transplantation. Radiotherapy-induced testicular damage from direct or scatter irradiation is dose dependent. Germinal epithelium is more susceptible in the sexually mature testes, whereas Leydig cells are more radiosensitive in the prepubertal testes. The stage of germ cell differentiation also affects radiosensitivity; hence, spermatogonia are damaged by doses as low as 0.1 Gy, whereas spermatids are affected at doses of 4 to 6 Gy. The recovery of spermatogenesis occurs as early as 9 to 18 months after irradiation when the dose is less than 1 Gy but can take more than 5 years with doses above 4 Gy. Chemotherapy-induced testicular damage and recovery are likewise dependent on the specific cytotoxic drug and the dose administered. Alkylating agents such as melphalan, cyclosphosphamide, chlorambucil, and busulfan; antimetabolites such as cytarabine and vinca alkaloids; and other cytotoxic agents such as cisplatin and procarbazine are all gonadotoxic. The germinal epithelium is more sensitive than Leydig cells; thus, azoospermia or oligospermia may be present despite normal or low-normal testosterone secretion. In animals, suppression of testicular function with GnRH analogues alone or with testosterone or flutamide, and with testosterone alone or with estradiol reduces the extent of testicular damage from chemotherapy or radiation. Similar clinical trials in humans have been less effica-
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cious. Other experimental techniques in animals include testicular biopsy to collect and cryopreserve stem cells before starting therapy for later implantation. In humans, semen collection and cryopreservation is possible in older adolescents and adults but not feasible in prepubertal boys. Mumps orchitis is rare since the institution of routine measles, mumps, and rubella (MMR) vaccination. Moreover, prepubertal children with mumps are rarely affected and, if so, usually have unilateral involvement (80%) rather than the bilateral orchitis that occurs in adults. Treatment with interferon-α2B can prevent the testicular atrophy and fibrosis that occurs in 30% to 50% of affected individuals. Other viral infections, such as coxsackievirus infection and dengue, also cause orchitis with residual testicular damage, whereas the orchitis caused by Epstein-Barr virus, adenovirus, echovirus, varicella, and influenza usually resolve without significant sequelae. Prenatal testicular torsion causes irreversible testicular injury, often resulting in complete testicular loss with only fibrotic tissue remaining. Testicular torsion after birth is an emergency mandating immediate surgical intervention to preserve testicular blood flow and function. Occasionally testes are damaged during surgical repair of cryptorchid testes, particularly high positioned abdominal testes. Some cryptorchid testes, however, are intrinsically malformed with impaired androgen secretion and spermatogenesis. Traumatic insults to the testes may also damage the testes and cause testicular failure. Liver cirrhosis is an uncommon etiology of hypogonadism in prepubertal boys. Chronic liver disease inhibits testosterone synthesis and increases SHBG levels, resulting in reduced free testosterone levels. Gonadotropins are initially high but become suppressed with liver failure. Chronic renal failure is also associated with primary testicular failure and elevated gonadotropins. Sickling of red cells within the testicular blood vessels damages the testes in patients with sickle cell anemia. Many intersex disorders are associated with primary gonadal failure due to defective testis formation, the inability to synthesize or respond to androgens, or prophylactic gonadectomy because of increased risk for malignancy (discussed in Intersex Disorders).
Females (Primary Ovarian Failure) Turner Syndrome
Turner syndrome due to haploinsufficiency of X chromosome genes is the most common sex chromosome anomaly and the major cause of primary hypogonadism in females. The presence of normal cell lines in fetal membranes is believed to be essential for placental function and fetal survival; thus, up to 15% of 45,X conceptuses are
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spontaneously aborted. Consequently, although 3 of 100 female conceptuses have a 45,X karyotype, only 1 in 2000 to 5000 liveborn females have this karyotype. If Turner syndrome is diagnosed prenatally, fetal echocardiography and ultrasonography are recommended to identify cardiac and renal structural anomalies and cystic hygromas, which increase the risk for fetal demise. In the absence of nuchal lymphedema, physical signs of Turner syndrome are usually minimal. During counseling, the wide variability in presentation of somatic features and the high probability of short stature and ovarian failure should be discussed. Clinical Features At birth, the diagnosis of Turner syndrome is suggested by swelling of the hands or feet from congenital lymphedema, a low hairline with excess nuchal skin and webbing (pterygium coli), ear deformities, dysplastic nails, a broad chest with hypoplastic nipples, and cardiac or renal malformations. Bicuspid aortic valves and aortic coarctation are the most common cardiac anomalies. After the newborn period, growth failure and lack of pubertal development or amenorrhea are the most common symptoms bringing this disorder to medical attention. Other associated features include cubitus valgus, multiple pigmented nevi, a high arched palate, short fourth metacarpals, defective dentition, scoliosis, idiopathic hypertension, and recurrent otitis media. Cognitive function is usually normal, although visuospatial organization may be affected and attention deficit is not uncommon. In addition to short stature and gonadal failure, endocrine manifestations include autoimmune thyroiditis, glucose intolerance, insulin resistance, and osteoporosis. Short stature and gonadal dysgenesis are the most consistent findings in Turner syndrome; associated somatic features may be minimal. Even when other features are absent, unexplained growth failure in girls should prompt cytogenetic studies to rule out this disorder. The short stature has been linked to haploinsufficiency of the SHOX (short stature homeobox–containing gene on the X chromosome) gene in the pseudoautosomal region at distal Xp. Growth velocity decelerates to subnormal rates by 2 to 4 years of age, although growth failure may first manifest during infancy. A pubertal growth spurt is absent. Ten percent of girls with Turner syndrome have scoliosis, which contributes to the short stature. Mean adult height of women with Turner syndrome is almost 20 cm below the population mean but correlates strongly with mid-parental height. Management At diagnosis, echocardiography or magnetic resonance imaging is recommended to assess cardiac status. Fifty percent of affected children have bicuspid aortic valves, and up to 20% have coarctation of the aorta. Echocardiograms
should be repeated every 5 years to monitor the diameter of the aortic root, as dilatation can occur even without structural abnormalities. Renal ultrasonography is recommended to identify aberrant vasculature and abnormalities in the collecting system or in the structure and position of the kidneys (e.g., horseshoe kidney). Despite normal growth hormone responses to provocative testing, growth hormone therapy has improved growth rates and adult height in girls with Turner syndrome and is the standard of care in the United States. Provocative growth hormone testing is not indicated before starting therapy. The suggested dose of recombinant human growth hormone is 0.35 to 0.375 mg/kg/week given as daily subcutaneous injections, but lower doses also substantially improve growth velocity. Prompt initiation of growth hormone therapy at the onset of growth failure is likely to offer the best outcome for improving final height. The use of growth hormone in girls with Turner syndrome has been associated with disproportionate growth of the hands and feet, more episodes of otitis media, and an increase in size and number of pigmented nevi. Most girls with Turner syndrome have primary gonadal failure and require exogenous estrogen for sexual maturation. The duration of growth hormone therapy before initiating estrogen replacement is a positive predictor of final adult height. This beneficial aspect of postponing estrogen therapy must be weighed against its deleterious effects on bone mineralization and the psychosocial stress of delayed sexual maturation. We advocate starting low-dose estrogen at 12 to 14 years of age and slowly increasing the dose over 2 to 3 years to achieve pubertal maturation at a normal pace. Conjugated estrogens (Premarin) 0.3 mg every other day or 5 μg ethinyl estradiol daily for 12 months is followed by 0.3 mg of Premarin or 10 μg ethinyl estradiol daily for the next 12 months. The estrogen dose is increased to Premarin 0.625 mg or 20 μg ethinyl estradiol before adding 5 mg medroxyprogesterone acetate (Provera) for 12 days each month to initiate cyclical uterine bleeding. Transdermal estrogen patches are now available in sufficiently low doses to allow gradual induction of puberty. One study has shown improved uterine development with transdermal estrogen therapy compared with oral estrogen. With timely initiation of GH and estrogen therapy, an adult height of 150 cm is a reasonable goal in most girls with Turner syndrome. Approximately 5% of girls with Turner syndrome have Y chromosomal material; this possibility needs to be considered in all virilized girls. The risk of gonadoblastoma is increased in patients with an intact Y chromosome or with pericentromeric fragments or markers for the Y chromosome; these patients should have prophylactic removal of the gonads.
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Girls with Turner syndrome have viable oocytes in fetal life and infancy but undergo accelerated oocyte loss. Residual ovarian function is sufficient in 15% to 25% of girls to initiate breast development, but only 5% to 10% progress to spontaneous menarche, and pregnancies are reported in only 1% to 3%. Elevated and/or rising gonadotropin levels are associated with progressive ovarian failure. Contraceptive and genetic counseling should be offered to individuals with residual ovarian function. Pregnancies are associated with a high risk of spontaneous miscarriages (26%) and stillbirths (6%). Thirty percent of live-born infants have various congenital anomalies, including Down syndrome, spina bifida, and congenital heart disease, and 35% have Turner syndrome; therefore, amniocentesis is recommended for all pregnant women with this syndrome. In vitro fertilization techniques using donated oocytes have reported success rates as high as 50% to 60%. Children born after oocyte donation have no additional risks. Cryopreservation of oocytes harvested early in life for later implantation is an area of ongoing research interest. Osteopenia is common in women with Turner syndrome. During childhood, cortical sites are affected to a greater extent than trabecular sites, and the defect is one of impaired bone formation. During adolescent and adult years, trabecular sites are more affected due to increased bone turnover. Long-term treatment with growth hormone in the prepubertal and early to midpubertal years optimizes bone mineral density and may potentiate attainment of peak bone mass when estrogen is provided. Estrogen replacement, adequate calcium intake (≥1.2 g/day), and weight-bearing activities all help promote bone mineralization. Autoimmune thyroiditis occurs in 10% to 30% of girls with Turner syndrome; thus, annual screening for elevations in thyroid stimulating hormone is recommended. Glucose intolerance and insulin resistance are common, but the incidence of diabetes mellitus is not increased and screening for glucose tolerance is not routinely recommended. Both growth hormone treatment and obesity exacerbate insulin resistance; hence, weight control is helpful. Recurrent otitis media resulting from anatomical malformations of the eustachian tubes should be treated aggressively to avoid the frequent development of conductive hearing loss. Continued screening for auditory deficits is recommended as progressive sensorineural hearing loss in the 1500- to 2000-Hz range may develop as the patient becomes older. Autoimmune Ovarian Failure
Autoimmune ovarian failure is a component of the autoimmune polyglandular syndromes (APGS) and has been reported in both types I and II. Sixty percent of girls
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older than 13 years of age with the type I syndrome (Addison disease, hypoparathyroidism, and candidiasis) develop ovarian failure, which may precede the onset of Addison disease by 8 to 14 years. Ten percent of individuals with type II APGS develop premature ovarian failure. Steroid cell antibodies (St-C-Ab) are detectable in 78% of women with premature ovarian failure who also have Addison disease. A lymphoplasmacellular infiltrate is evident around steroid-producing cells, and the ovaries may appear cystic, possibly due to the high levels of gonadotropins. Associated autoimmune disorders are present in more than one third of girls and women with autoimmune ovarian failure. Autoimmune thyroid disease is the second most prevalent endocrinopathy, followed by Addison disease. Other associated conditions are pernicious anemia, diabetes mellitus, and myasthenia gravis. No antibody markers are available to diagnose autoimmune ovarian failure in humans, although a gene encoding an ooplasm-specific antigen has been isolated in mice with autoimmune oophoritis. It has been designated MATER (Maternal Antigen That Embryos Require) based on its role in preimplantation development. Immunization of rabbits with heterologous zona pellucida antigens also causes immune destruction of ovarian follicles. Short courses of high-dose glucocorticoids, cyclosporin A and plasmapheresis have resulted in temporary improvement of the autoimmune ovarian failure. Mutations in the Luteinizing Hormone and FollicleStimulating Hormone Genes and Receptors
In females, isolated FSH deficiency (elevated FSH, low LH and estradiol) presents as delayed puberty and/or infertility with impaired follicular development. Although GnRH stimulates a rise in LH but not FSH, exogenous FSH has successfully induced fertility in at least one woman with this defect. Homozygous mutations in the FSHb gene have been identified; the most common is a 2-bp deletion (Val61X) in exon 3, a frameshift mutation that causes premature termination. The truncated FSH is unable to dimerize or bind to the FSH receptor and has decreased immunoactivity and bioactivity. Missense mutations have also been identified. Two main phenotypes have been reported in individuals carrying an inactivating mutation of the FSH receptor gene. The first is the Finnish phenotype associated with a homozygous Ala189Val mutation, which affects receptor trafficking to the cell surface. Females with this mutation have absent or poorly developed secondary sexual characteristics, primary amenorrhea, and high gonadotropins. Ovaries are small and have only primordial and primary follicles. In the other phenotype, a partial defect exists in FSH
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receptor signaling. Women with this defect have primary amenorrhea with low estrogen and high FSH. The ovaries are of normal size with antral follicles that develop to varying extents depending on the severity of the functional defect in the receptor. The 46,XX individuals with mutations in the LH receptor present with amenorrhea but develop secondary sexual characteristics. Gonadotropins are elevated, whereas estradiol and progesterone are low. Follicles develop only to the antral stage, suggesting a role for LH in late follicular maturation. Miscellaneous Causes of Ovarian Dysfunction
Premature ovarian failure occurs in 50% of individuals exposed to pelvic irradiation for malignant disease. The severity and duration of ovarian dysfunction depend on the radiation dose and fractionation and on age at time of treatment. The LD50 for oocytes is about 4 Gy; exposure to more than 8 Gy causes permanent ovarian failure. Radiation damage causes interstitial fibrosis, hyalinization of blood vessels, and developmental arrest and reduced numbers of primary follicles. Surgical repositioning of the ovaries behind the uterus or laterally to the paracolic gutters to reduce radiation exposure has successfully preserved ovarian function. Cytotoxic chemotherapy causes less impairment of gonadal function in females than in males; however, premature ovarian failure still occurs in more than 60% of treated women. Gonadotoxic agents include cyclophosphamide, busulfan, procarbazine, and etoposide. The actively proliferating cells in the mature ovary are more sensitive to cytotoxic chemotherapy than the nondividing cells in the prepubertal ovary. GnRH analogues have been used successfully to induce a prepubertal milieu during chemotherapy with alkylating agents, with spontaneous resumption of ovulation and menses in most long-term survivors. Antiestrogens and oral contraceptives have also been used before chemotherapy for the same purpose. Gonadal suppression thus merits consideration in all reproductiveage females undergoing chemotherapy. Egg retrieval for in vitro fertilization and embryo cryopreservation are viable methods of preserving fertility for married couples but are not feasible in young girls. As an alternative, cryopreservation of ovarian sections for autotransplantation is under clinical investigation, although the theoretical risk of reintroducing malignant stem cells raises concerns. Certain chemicals and environmental toxins may cause ovarian damage, such as 2-bromopropane, a cleaning solvent, which caused ovarian failure in 16 Korean laborers. With the implementation of routine MMR vaccination, mumps oophoritis has become an extremely uncommon cause of hypergonadotropic ovarian failure. Ovarian failure has also been associated with Shigella infections, malaria, and varicella.
In the classic form of galactosemia, a deficiency in uridine diphosphate galactose causes ovarian damage starting during intrauterine life. Steroidogenic defects in estradiol synthesis such as mutations of the genes for steroidogenic acute regulatory protein (StAR), 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, and aromatase are discussed in Chapter 7.
Eugonadal Primary Amenorrhea (With Normal Breast and Pubic Hair Development) Partial or Complete Noncanalization of the Vagina; Imperforate Hymen
Girls with vaginal agenesis or an imperforate hymen often have cyclical endometrial shedding that accumulates in the uterus and fallopian tubes due to outflow obstruction (cryptomenorrhea). Secondary sexual characteristics are generally well developed, but menarche fails to occur. A history of cyclical lower abdominal pain is often elicited. The müllerian structures become distended and painful from accumulated menstrual blood and may be palpable on abdominal examination. A vaginal examination and ultrasonogram are diagnostic. Surgery is necessary to correct the anatomical obstruction to menstrual flow. Evaluation Evaluation of pubertal delay should include a careful history of general health and nutrition, growth pattern, neurological symptoms, anosmia, past history of radiation, chemotherapy or surgery, exercise intensity, and family history of the onset and pattern of pubertal development (absent, delayed onset, “stalled puberty”). On physical examination, a careful standing height with upper-to-lower segment ratio and arm span (for early detection of an eunuchoid habitus), assessment of subcutaneous fat, pubertal staging including testicular size and position in boys, a test for anosmia, and a complete neurological assessment are particularly important. The growth pattern should be assessed with serial heights plotted on a growth chart and compared with standard curves for “late maturers.” A complete blood count, sedimentation rate, and biochemical profile help exclude chronic diseases. Simultaneous slowing of growth should prompt measurement of thyroid function and insulin-like growth factor-I to identify associated endocrine dysfunction. Prolactinomas sometimes present as stalled puberty; thus, a prolactin level should be included in the evaluation. DHEAS, sex steroids (testosterone or estradiol using ultrasensitive assays), FSH, and LH provide an assessment of the HPG axis. A karyotype should be obtained in children with hypergonadotropic hypogonadism to rule out Klinefelter or Turner syndrome.
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If gonadotropins are low without an obvious cause of hypogonadotropic hypogonadism such as unequivocal anorexia nervosa or a systemic illness, cranial magnetic resonance imaging with gadolinium for pituitary imaging is essential to identify intracranial pathology. A pelvic sonogram may be able to delineate müllerian structures and define the nature of the gonads. A bone age is helpful for determination of skeletal maturation in relation to growth and pubertal development. GnRH stimulation testing does not differentiate between constitutional delay in puberty and IHH: a family history of constitutional delay and a growth pattern suggestive of a “late bloomer” usually point to the former condition. Although routine GnRH testing is not diagnostic, clinical studies suggest that the gonadotropin response to potent GnRH agonists or to GnRH after priming with GnRH for 36 hours may differentiate between the two conditions.
MANAGEMENT OF AND TREATMENT OPTIONS FOR DELAYED PUBERTY Delayed puberty secondary to systemic illness, excessive exercise, or weight loss can be corrected with treatment or resolution of the primary disorder. If puberty does not resume in a timely fashion, sex steroid therapy can be initiated to induce puberty. The therapeutic goals are to induce age- and gender-appropriate secondary sexual characteristics and improve psychosocial health. Estrogen or testosterone therapy also induces a pubertal growth spurt and improves bone mineralization. To avoid rapid epiphyseal closure, initial therapy is begun at doses that are well below adult replacement doses and then gradually increased to achieve pubertal maturation at a normal pace. Long-term sex steroid therapy in individuals with persistent hypogonadism helps maintain an eugonadal state and optimize bone mineralization.
Hormone Replacement Therapy in Males Puberty Induction and Maintenance
In boys, treatment is started at 12 to 14 years of age or, in older individuals, at the time of diagnosis. Testosterone enanthate or cypionate is started at a dose of 50 mg intramuscular every 4 weeks and increased by 25 to 50 mg every 6 to 12 months to a maximum of 200 mg every 2 to 3 weeks. Accelerated bone age advancement and growth rate are indications for decreasing the dose. Severe acne, fluid retention, and prolonged painful erections also mandate dose reduction. Local side effects include tenderness at the injection site and allergic reactions to the vehicle (sesame or cottonseed oil). Another option is the use of a daily trans-
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dermal gel or patch that avoids the high peaks and troughs observed with depot testosterone injections. The transdermal formulations, however, are designed to provide adult androgen replacement; therefore, the lower doses needed for induction of puberty have not been established. Androgel 1% (Unimed Pharmaceuticals, Inc., Deerfield, IL) is dispensed in packets of 2.5 or 5 g that deliver 25 or 50 mg of testosterone when applied to the shoulders, upper arms, or abdomen. Androderm (Watson Pharmaceuticals, Inc., Corona, CA) patches for nonscrotal areas deliver 2.5 or 5 mg of testosterone daily. Testoderm (Alza Pharmaceuticals, Palo Alto, CA) is available for scrotal skin as either Testoderm (4or 6-mg delivery system) or Testoderm with adhesive (6 mg) and, for nonscrotal areas, as Testoderm TTS (5 mg). Doses are adjusted on the basis of testosterone levels obtained after 2 to 3 weeks of use. Recommended sampling times are the morning after applying Androgel or the Androderm patch and 2 to 4 hours after applying any of the Testoderm patches. Local skin irritation can be minimized with topical steroids. Disadvantages of the transdermal patches include difficulty with adhesion in individuals involved in strenuous physical activity and cross-transfer of testosterone to other individuals from skin contact. In boys with hypogonadotropic hypogonadism and functional testes, low-dose hCG can be used as an alternative to testosterone in a dosage of 200 to 500 units administered every other day. Although this regimen has the advantage of increasing testicular size, thus providing cosmetic benefits, the obvious disadvantage is the frequency of administration. Moreover, excessive stimulation of Leydig cells also increases estrogen production, which causes gynecomastia. This is avoided by using the lowest effective dose of hCG. In patients with constitutional delay of growth and puberty, a short course of low-dose testosterone is often sufficient to initiate pubertal maturation, improve growth rate, and alleviate psychosocial distress. Spontaneous progression of puberty often ensues when therapy is discontinued after 6 months. The experimental addition of letrozole, an aromatase inhibitor, to monthly testosterone enanthate injections has been demonstrated to improve adult predicted height in boys with constitutional delay of growth and puberty. Induction of Fertility
Fertility in patients with hypogonadotropic hypogonadism requires treatment with gonadotropins or pulsatile GnRH therapy. Pulsatile GnRH (pulse frequency every 2 hours) is effective in inducing testicular growth and spermatogenesis in individuals with hypothalamic defects, but gonadotropins are the treatment of choice if the pituitary is dysplastic or has sustained extensive damage. hCG and recombinant FSH/human menopausal gonadotropins with hCG have all been used successfully.
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Hormone Replacement Therapy in Females Puberty Induction and Maintenance
Low-dose estrogen therapy is initiated at 10 to 12 years of age to induce breast budding without advancing bone age. Initiation of estrogen therapy is delayed in girls with Turner syndrome to 12 to 14 years to optimize the effects of growth hormone therapy. The initial dosage of estrogen is either 0.3 mg conjugated estrogens every other day or 5 μg of ethinyl estradiol daily. Transdermal estrogen patches (delivering 0.025 mg/day) applied twice weekly are also available for induction of breast development. Transdermal estrogen is useful in children with poor compliance and in those with a family history of thromboembolism. The dose of estrogen is increased gradually every 6 to 12 months to achieve full replacement doses within 2 to 3 years. Full estrogen replacement at a dose of 0.625 mg conjugated estrogens or 20 μg ethinyl estradiol ensures maintenance of feminization and protection against osteoporosis. Cyclical progesterone (5-10 mg daily of medroxyprogesterone acetate or 200-400 mg micronized progesterone [Prometrium, Solvay Pharmaceuticals, Inc., Marietta, GA]) is added for 12 days every month after full estrogen replacement to ensure cyclical endometrial shedding and decrease the risk of endometrial dysplasia. If pubertal delay results from chronic illnesses, undernutrition, or excessive exercise, treatment is directed at the primary condition. When hyperprolactenemia is the cause of pubertal delay, hypothyroidism should be excluded, and a cranial imaging study is necessary to identify prolactinomas. Therapy is then initiated with the dopamine agonists bromocryptine mesylate or cabergoline. Starting bromocryptine at a low dose of 1.25 mg at bedtime minimizes the major side effect of nausea. The dose is then increased gradually to 2.5 mg BID or TID to normalize the prolactin levels. Cabergoline has the advantage of biweekly administration and fewer side effects. It is begun at a dosage of 0.25 mg twice weekly and may be gradually increased to 1 mg twice weekly, if required. Androgens may be helpful for inducing hair growth in girls lacking pubic hair, but male pattern baldness, clitoral enlargement, and voice changes are possible side effects. Induction of Fertility
Pulsatile GnRH therapy using a pulse frequency that mimics that seen across a menstrual cycle is effective in inducing ovulation in women with hypothalamic hypogonadism. When hypogonadism is due to pituitary dysfunction, either hCG or human menopausal gonadotropin (hMG)/recombinant FSH with hCG is used. GnRH therapy has the advantage of higher conception rates with fewer multiple pregnancies.
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MAJOR POINTS
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In girls, puberty is considered delayed if breast development has not started by age 13, or with failure to attain menarche and immature breast development at age 15. Primary amenorrhea is defined as failure to attain menarche by age 16 in the presence of normal breast development. In boys, puberty is considered delayed in the absence of testicular enlargement (>4 mL) or pubic hair at age 14. In addition to delay in the onset of puberty, an unusually slow pace of puberty or arrested pubertal development warrants further evaluation to exclude pathology. Pubertal delay can result from hypogonadotropic hypogonadism (hypothalamic or pituitary dysfunction or immaturity), hypergonadotropic hypogonadism (low sex steroids with a normal compensatory rise in gonadotropins), or eugonadotropic hypogonadism (structural defects in the development of the uterus, cervix, and vagina). Hypogonadotropic hypogonadism encompasses the most frequent cause of pubertal delay in boys—constitutional delay of growth and development—but also includes a number of pathological etiologies. The diagnosis of constitutional delay is a diagnosis of exclusion. The association of anosmia with pubertal delay (hypogonadotropic hypogonadism) is highly suggestive of Kallmann syndrome. Hypergonadotropic hypogonadism (low sex steroids and elevated follicle-stimulating hormone and luteinizing hormone) is diagnostic of a pathological cause of delayed puberty. Turner syndrome needs to be considered in a short girl with pubertal delay (hypergonadotropic hypogonadism), especially in the absence of a family history of delayed puberty. An enuchoid habitus, slow or delayed puberty (with normal or elevated follicle-stimulating hormone), and relatively small testes for the degree of pubertal maturation are suggestive of Klinefelter syndrome. The optimal timing for gonadal steroid replacement to induce puberty is dependent on the growth and skeletal maturation of the adolescent. Ideally, testosterone or estrogen is started at a low dose and gradually increased at a pace similar to endogenous puberty until adult replacement doses are achieved.
SUGGESTED READINGS Ackermann JC, Weiss J, Lee EJ, et al: Inherited disorders of gonadotropin hormones, Mol Cell Endocrinol 2001;179:89. American Academy of Pediatrics, Committee on Genetics: Health supervision for children with Turner syndrome, Pediatrics 1995;96:1166. Amory JK, Anawalt BD, Paulsen CA, et al: Klinefelter syndrome, Lancet 2000;356:333. Argente J: Diagnosis of late puberty, Horm Res 1999;51(suppl 3):95.
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Blumenfeld Z, Haim N: Prevention of gonadal damage during cytotoxic therapy, Ann Med 1997;29:199.
Saenger P: Growth promoting strategies in Turner syndrome, J Clin Endocrinol Metab 1999;84:4345.
Brook CGD: Treatment of late puberty, Horm Res 1999;51(suppl 3):101.
Seminara SB, Oliveira LMB, Beranova M, et al: Genetics of hypogonadotropic hypogonadism, J Endocrinol Invest 2000;23:560.
de Roux N, Milgrom E: Inherited disorders of GnRH and gonadotropin receptors, Mol Cell Endocrinol 2001;179:83.
Smyth CM, Brenner WJ: Klinefelter syndrome, Arch Intern Med 1998;158:1309.
DiMeglio LA, Pescovitz OH: Disorders of puberty: inactivating and activating mutations, J Pediatr 1997;131:S8.
Styne DM: New aspects in the diagnosis and treatment of pubertal disorders, Pediatr Endocrinol 1997;44:505.
Hayes FJ, Seminara SB, Crowley WF Jr: Hypogonadotropic hypogonadism, Endocrinol Metab Clin North Am 1998;27:739.
Wickman S, Sipila I, Ankarberg-Lindgren C, et al: A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomized controlled trial, Lancet 2001;357:1743.
Howell S, Shalet S: Gonadal damage from chemotherapy and radiotherapy, Endocrinol Metab Clin North Am 1998;27:927. Kulin H: Delayed puberty, J Clin Endocrinol Metab 1996;81:3460. Layman LC: Genetics of human hypogonadotropic hypogonadism, Am J Med Genet 1999;89:240. Palmert MR, Boepple PA: Variation in the timing of puberty: clinical spectrum and genetic investigation, J Clin Endocrinol Metab 2001;86:2364.
Wu FCW, Brown DC, Cutler GE, et al: Early morning plasma testosterone is an accurate predictor of imminent pubertal development in prepubertal boys, J Clin Endocrinol Metab 1992;76:26. Yen SSC: Effects of lifestyle and body composition on the ovary, Endocrinol Metab Clin North Am 1998;27:915.
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7
Introduction Gonadal Determination and Sex Differentiation Primitive Undifferentiated Gonad Testicular Differentiation Ovarian Differentiation Differentiation of the Genital Ducts Differentiation of the External Genitalia Müllerian Inhibiting Substance and Testosterone Differential Diagnosis of Intersex Conditions Disorders of Gonadal Morphogenesis Complete or Partial Gonadal Dysgenesis Mixed Gonadal Dysgenesis True Hermaphroditism Congenital Anorchia or the Vanishing Testes Syndrome Virilization in a Genetic Female (Female Pseudohermaphroditism) Congenital Adrenal Hyperplasia Other Virilizing Forms of Congenital Adrenal Hyperplasia Aromatase Deficiency In Utero Exposure to Androgens or Progestational Agents Undervirilization in a Genetic Male (Male Pseudohermaphroditism) Defects in Testosterone Biosynthesis Leydig Cell Hypoplasia (Inactivating Mutations of the Luteinizing Hormone Receptor) Androgen-Insensitivity Syndromes Gonadotropin, Growth Hormone, or Human Chorionic Gonadotropin Deficiency Miscellaneous Causes of Undervirilization Congenital Embryopathy Evaluation History and Examination Laboratory Studies Imaging Studies Management of and Treatment Options for Intersex Disorders Conclusion Major Points
Intersex Disorders MADHUSMITA MISRA MARY M. LEE
INTRODUCTION The designation of a newborn infant as a boy or girl is usually evident from the appearance of the external genitalia at delivery. Parents and medical personnel seldom anticipate that the process of sex differentiation may go awry, making gender indeterminate at birth. When the phenotype of the external genitalia is ambiguous or discordant with fetal ultrasonogram or prenatal karyotype, concerns arise about a potential intersex condition. In these children, clinical decisions regarding sex assignment and long-term management of gender role remain challenging, despite tremendous advances during the past decade in understanding the basic biology of gonadal determination and sex differentiation.
GONADAL DETERMINATION AND SEX DIFFERENTIATION The progression of molecular events in gonadal determination and sex differentiation is being defined more precisely as an increasing number of genes in these developmental pathways are identified (Figure 7-1). Chromosomal (46,XX or 46,XY) or genetic sex is established at fertilization with the Y chromosome carrying the primary determinant of the male-specific pathway, the testis-determining gene (SRY). Before induction of SRY expression, however, XX and XY embryos are morphologically undifferentiated and have common embryological precursors of the gonads and external genitalia and both sets of internal genital ducts.
Primitive Undifferentiated Gonad Primitive germ cells are first recognizable in the dorsal endoderm of the yolk sac at 3 to 4 weeks’ gestational age. 103
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Urogenital ridge WT1 SF-1 LIM1 XY male
SRY SOX-9
Bipotential gonad
Male sex differentiation
Testis
Sertoli cells
Leydig cells
SF-1 WT-1 MIS
Ovary
Female sex differentiation
Müllerian duct differentiation (uterus, fallopian tubes, cervix, upper vagina)
SF-1 Testosterone
wölffian duct degeneration DHT
Müllerian duct regression
XX female
WNT-4 DAX-1
wölffian duct differentiation (epididymis, vas deferens, seminal vesicle)
External genital virilization (penis, prostate, scrotum)
Figure 7-1 Pathways of Gonadal Determination and Sex Differentiation. Sequential events leading from the undifferentiated urogenital ridge to a fully differentiated male or female are depicted on this flow diagram. Some of the genes involved in gonadal formation and testicular and ovarian differentiation are shown.
During the next 2 weeks, these cells migrate to the hindgut and then through the dorsal mesentery to populate the primitive gonad that has arisen from the mesoderm of the urogenital ridge. A number of genes have been revealed as key players in formation of the undifferentiated gonad through finding the phenotype of gonadal agenesis in genetically engineered mice with null mutations of these genes. Of these, two transcription factors, WT1 (the product of the Wilms’ tumor suppressor gene) and steroidogenic factor-1 (SF-1), are the best characterized. WT1 is essential for kidney and gonad morphogenesis, whereas SF-1 plays a critical role in development of the adrenal gland, pituitary, and gonad. After initial gonadogenesis, WT1 and SF-1 are postulated to activate other downstream genes that regulate sex-specific gonadal determination, such as DAX-1 and SRY. A heterozygous loss of function mutation of WT1 (11p13) in humans causes the WAGR contiguous gene syndrome (Wilms’ tumor, aniridia, mental retardation, and minor genitourinary abnormalities). A less common but more severely affected phenotype is associated with dominant negative point mutations in the zinc finger region of WT1 that abrogate DNA binding to the wild-type allele. The phenotype associated with these dominant negative mutations is the Denys-Drash syndrome, characterized by Wilms’ tumor, diffuse mesangial sclerosis leading to end-
stage renal failure in the first few years of life, and genital ambiguity. The gonadal phenotype varies from complete sex reversal in 46,XY individuals (streak gonads and female genitalia) to genital ambiguity with dysgenetic gonads and undervirilization. A similar gonadal phenotype of gonadal dysgenesis and genital ambiguity is present in Frasier syndrome, which is caused by mutations within intron 9 of the WT1 gene. In this related syndrome, Wilms’ tumor does not develop and patients develop focal glomerular sclerosis with a less severe renal impairment that is of later onset. SF-1 is initially expressed in the undifferentiated urogenital ridge, where it acts in concert with WT1 to induce gonadal and adrenal formation. At later developmental stages, SF-1 is upregulated in the differentiating testis and repressed in the ovary to regulate somatic cell differentiation and induce steroidogenic enzyme expression in both adrenals and gonads. The phenotype of gonadal agenesis and male-to-female sex reversal with an Sf-1 mutation is similar to that of Wt1. In contrast to the renal abnormalities found with a deletion of Wt1, however, Sf-1 knock-out mice have defective hypothalamic and pituitary function and adrenal agenesis. In humans, the majority of SF-1 mutations may be lethal because of its essential role in the formation of the adrenal gland and production of all steroid hormones. The rare patients reported with SF-1 mutations manifest adrenal failure in infancy and 46,XY sex reversal.
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opment, or it may alter gene expression by bending DNA. The phenotype of patients with SRY loss of function mutations ranges from complete gonadal dysgenesis (46,XY sex reversal) to true hermaphroditism or partial gonadal dysgenesis with genital ambiguity and testicular dysgenesis. Conversely, a gain of function mutation resulting from a Y-to-X translocation bearing the SRY gene is responsible for some cases of 46,XX male sex reversal. SOX9 (17q24.3-25.1) is an SRY-related HMG box transcription factor that is critical for testicular determination. SOX9 is initially expressed at low levels in both male and female urogenital ridges in the bipotential embryo. As the gonads start to differentiate, the expression of SOX9 is induced in males and repressed in females, similar to that of SF-1. Its function in testicular determination is confirmed by the development of testes and sex reversal in XX mice transgenic for SOX9. Heterozygous SOX9 dominant negative mutations cause testicular dysgenesis and 46,XY sex reversal in humans. This gonadal phenotype is an inconsistent feature of campomelic dysplasia, a syndrome attributed to SOX9 mutations that is characterized by congenital bowing of long bones, brachydactyly, micrognathia, and congenital cardiac and renal anomalies. The inability to demonstrate translocation of the SRY gene in all patients with 46,XX sex reversal and the finding of intact SRY and SOX9 genes in some women with 46,XY
Testicular Differentiation The embryonic gonad remains indifferent until SRY is activated at day 42 to initiate the male developmental pathway (Figure 7-2; see Figure 7-1) During the next few days, testicular organization occurs as the primordial germ cells are incorporated into testicular cords. Within these primitive seminiferous cords, the primordial germ cells start to differentiate and proliferate in response to SRY. The somatic cells within the cords differentiate into Sertoli cells, whereas the interstitial mesenchymal cells differentiate into Leydig cells, the two major hormone-producing cell types of the testis (see Figure 7-2). The identification of SRY as the primary testisdetermining gene was accomplished by positional cloning in patients with XX sex reversal. Its role in testis determination was subsequently confirmed by the generation of sex-reversed XX mice transgenic for Sry, a Sox family transcription factor with a high mobility group (HMG) DNAbinding motif. The HMG box is the site of numerous SRY (Yp11.3) mutations causing human 46,XY sex reversal, verifying the importance of this region for SRY action. Although specific gene targets of SRY have not been identified, experimental data support several possibilities for its mechanism of action: SRY may be a classic transcriptional activator, it may repress genes that inhibit testicular devel-
Sertoli cell activity
Leydig cell activity
Testosterone
Testis descent Male external genital differentiation
External genital growth
SRY wölffian duct differentiation
Germ cell migration 4
5
Müllerian duct regression 6
7
8
9
10
11
12
13
14
15
40
Gestation (weeks) Figure 7-2
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Temporal Pattern of Events in Male Sex Differentiation. During the period of germ
cell migration, undifferentiated wölffian and müllerian ducts are formed in all embryos. The onset of SRY expression at 6 weeks stimulates organization of the testes and differentiation of the Sertoli and Leydig cells. Sertoli cell activity refers to the secretion of müllerian inhibiting substance to induce müllerian duct regression, and Leydig cell activity refers to the secretion of testosterone to promote male sex differentiation, with the increase in fetal serum testosterone concentrations represented by the dark line. (Adapted with permission from Hughes LA: Minireview: sex differentiation, Endocrinology 2001;142:3281.)
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sex reversal reinforce the role of other genes in the testicular determination pathway. Such genes are likely to be found within small chromosomal deletions such as 9p24, 10q, and 12q13 that are present in patients with SRYindependent 46,XY sex reversal or gonadal dysgenesis. Candidate genes include DMRT (9p23.3-24.1), a testicular gene essential for Sertoli cell development, and Dhh (Desert hedgehog, 12q13.1), a gene critical for Sertoli cell–germ cell interactions and germ cell maintenance.
4 may act in concert with DAX-1 to antagonize SRY action and promote ovarian differentiation. Although WNT-4 knock-out mice have XX sex reversal, this association has not been reported in humans. Mutations or deletions of DAX-1 cause congenital adrenal hypoplasia and hypogonadotropic hypogonadism, while gonadal development is unaffected. However, a duplication of either WNT-4 or DAX-1 can interfere with normal testicular development to cause gonadal dysgenesis as a dosage-dependent form of 46,XY sex reversal.
Ovarian Differentiation In female embryos, the primitive gonad remains undifferentiated until the ninth week of gestation when ovarian determining factors such as Wnt-4 and DAX-1 initiate ovarian differentiation. The dividing germ cells are loosely organized into irregular cords. The oocytes commence meiotic prophase but become arrested at the diplotene stage of prophase and are surrounded by somatic cells to form primordial follicles. Follicular development is maximal at 20 to 25 weeks’ gestation and occurs in parallel with differentiation of the somatic cells to granulosa or theca cells. Germ cells that are not incorporated into follicles undergo attrition to cause the decrease in number from 6 or 7 million to 2 million at term. Ovarian development requires the interactions of two genes, WNT-4, a secreted growth factor, and DAX-1, a nuclear hormone receptor in the DSS region (dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-linked) of the X chromosome (Xp21). WNT-4 and DAX-1 are both expressed in the undifferentiated gonad and then repressed in the developing testis and upregulated in the ovary. WNT-
Figure 7-3 Differentiation of the Male and Female Genital Ducts. Both sets of genital ducts are present in the indifferent stage and differentiate according to the local hormonal milieu from 7 to 12 weeks. Female development occurs in the absence of male hormones. Male development proceeds in response to the actions of testosterone on the wölffian ducts and müllerian inhibiting substance on the müllerian duct. (Reprinted with permission from Grumbach MM, Conte FA: Disorders of sexual differentiation. In Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams’ Textbook of Endocrinology, 10th ed, Philadelphia, 2003, WB Saunders.)
Differentiation of the Genital Ducts Sex differentiation of the wölffian (male) and müllerian (female) internal genital ducts depends on the local hormonal milieu (Figure 7-3; see Figure 7-2). As testicular cords organize in the differentiating testis, SF-1 and WT1 act cooperatively to activate the expression of müllerian inhibiting substance (MIS) in the Sertoli cells. MIS signals through the mesenchymal cells to indirectly stimulate apoptotic cell death of the müllerian duct epithelial cells in males. MIS-induced regression of the müllerian ducts starts by 8 weeks and is complete by the third month, leaving a vestigial remnant as the prostatic utricle. Shortly after the onset of MIS expression, SF-1 induces the expression of the cytochrome P450 steroid hydroxylases and 3β-hydroxysteroid dehydrogenase to initiate testosterone synthesis by Leydig cells. During this stage of gonadal development, testosterone production is gonadotropin independent. Testosterone has no direct action on the müllerian ducts but potentiates MIS actions to facilitate complete regression of the müllerian ducts. The high local concentrations of
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testosterone stimulate differentiation and growth of the wölffian structures (epididymis, vas deferens, seminal vesicles) between 9 and 14 weeks of embryonic life. In females, differentiation of the genital ducts occurs without a need for active production of hormones. Müllerian ducts differentiate into the Fallopian tubes, uterus, cervix, and upper vagina in the absence of MIS, whereas the wölffian ducts degenerate in the absence of testosterone (see Figure 7-3).
Differentiation of the External Genitalia In parallel with internal genital duct development, differentiation of the genital tubercle, urethral folds, and labioscrotal swellings takes place (Figure 7-4). In males, although testosterone is able to promote wölffian duct development, virilization of the external genital requires reduction of testosterone to its more active metabolite, dihydrotestosterone (DHT) by 5α-reductase-2. The expression of this
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enzyme at the undifferentiated genital tubercle and urogenital sinus enables testosterone to be converted to DHT at its site of action. DHT stimulates fusion of the urethral folds to form the corpora spongiosa enclosing the cavernous urethra and the labioscrotal swellings to form the scrotum. DHT also mediates prostate differentiation and growth of the genital tubercle into the glans penis. The critical window for genital virilization is before 12 weeks; androgen exposure after this time can cause hypertrophy of the phallus but not midline fusion (see Figure 7-2). Much of phallic growth occurs between 20 to 40 weeks, when testosterone production becomes dependent on pituitary luteinizing hormone (LH) stimulation. Descent of the testes into the scrotal sac is also a late event mediated in part by androgens. In the absence of androgens and MIS, differentiation of the genitalia proceeds independently of ovarian function and inherently follows the female pathway (see Figure 7-4). The fused müllerian ducts contact the urogenital sinus to
Figure 7-4 Differentiation of Male and Female External Genitalia. The external genitalia are initially identical in male and female embryos. Sexually dimorphic differentiation proceeds after gonadal determination and the secretion of testosterone by the fetal testis. Male development requires local conversion of testosterone to its more biologically active reduced product, dihydrotestosterone. Female development occurs in the absence of androgenic stimulation. Differentiation of the external genitalia is complete by 12 to 14 weeks. Exposure to androgen after this period manifests primarily as phallic enlargement (Reprinted with permission from Grumbach MM, Conte FA: Disorders of sexual differentiation. In Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams’ Textbook of Endocrinology, 10th ed, Philadelphia, 2003, WB Saunders.)
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form the müllerian tubercle. This stimulates endodermal proliferation and extension of the uterovaginal plate to the perineum to form a separate vaginal orifice. The plate canalizes to form the vagina at 20 weeks. The urogenital tubercle becomes the clitoris and the urethral and labioscrotal folds remain unfused and form the labia minora and majora.
Müllerian Inhibiting Substance and Testosterone To achieve normal differentiation of the internal and external genital structures in males, MIS and testosterone and their receptors, and downstream signaling pathways must be intact. MIS, or anti-müllerian hormone (AMH), is a 140-kDa glycoprotein in the transforming growth factor (TGF)-β family of growth and transcription factors. MIS is produced as a prohormone that undergoes proteolytic cleavage to generate a bioactive C terminus that binds to cell surface serine-threonine kinase receptors. Mutations in the MIS gene (19p) or its receptor (12q) result in the persistent müllerian duct syndrome. In affected males, the absence of normal MIS action enables the müllerian ducts to differentiate and persist as rudimentary or incompletely developed müllerian structures. The retained müllerian
Figure 7-5 Schematic of androgen action. Androgens diffuse into the cell and bind to the androgen receptor. The release of heat shock protein activates the androgen– receptor complex and enables it to be dimerized, which facilitates entry into the nucleus for transactivation of downstream genes. (Reprinted with permission from Grumbach MM, Conte FA: Disorders of sexual differentiation. In Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams’ Textbook of Endocrinology, 10th ed, Philadelphia, 2003, WB Saunders.)
structures interfere with testicular descent and often manifest as unilateral testicular ectopia with both testes descended through the same inguinal canal. Androgen synthesis is essentially unaffected; therefore, the wölffian ducts and external genitalia virilize normally. Male sex differentiation requires sufficient synthesis of testosterone at the appropriate time. Initial testosterone synthesis during the period of genital differentiation is gonadotropin independent, but continued production of testosterone in later pregnancy is dependent on human chorionic gonadotropin (hCG) or LH. Genetic mutations of any of the testosterone biosynthetic enzymes or the cholesterol transporter can diminish androgen production and disrupt masculinization of the internal and external genitalia. Inability to convert testosterone to DHT (5αreductase-2 gene defect) causes undervirilization of the external genitalia, but wölffian duct development remains normal. DHT and testosterone bind to the androgen receptor, a steroid hormone nuclear receptor. The androgen receptor is bound to chaperone (heat shock) proteins in the absence of ligand (Figure 7-5). Androgen binding produces a conformational change that releases the heat shock protein and activates the receptor. The activated steroid recep-
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tor complex dimerizes, enters the nucleus, and binds to steroid-responsive elements to elicit androgen-mediated transcriptional events. Androgen resistance due to a defect in the androgen receptor or signaling pathway causes varying degrees of undervirilization of both internal and external genitalia. All of these conditions affecting androgen synthesis or action are characterized by undervirilization of the genitalia with complete or nearly complete müllerian duct regression because MIS action is only minimally affected.
DIFFERENTIAL DIAGNOSIS OF INTERSEX CONDITIONS Classification of intersex conditions into four pathophysiological categories provides an organized framework for the
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evaluation of children with genital ambiguity (Table 7-1). These categories are as follows: 1. Abnormality in the primary process of gonadal morphogenesis 2. Virilized genetic female with ovaries (female pseudohermaphroditism) 3. Undervirilized genetic male with testes (male pseudohermaphroditism) 4. Congenital embryopathy independent of hormone production
Disorders of Gonadal Morphogenesis Primary defects in gonadal morphogenesis are often associated with a chromosomal anomaly or a mutation or deletion of one of the genes critical for gonadal formation and testicular differentiation. In general, the aberrant
Table 7-1 Differential Diagnosis of Intersex Conditions Disorders of Gonadal Morphogenesis
Gene Map Symbol (Locus)
Gonadal dysgenesis (partial and complete) Campomelic dysplasia Associated with primary adrenal failure Denys-Drash and Frasier syndromes Dosage-sensitive sex reversal Associated with polyneuropathy Mixed gonadal dysgenesis True hermaphroditism Congenital anorchia/vanishing testis syndrome Virilized female Congenital adrenal hyperplasia 21α-Hydroxylase deficiency 11β-Hydroxylase deficiency 3β-Hydroxysteroid dehydrogenase deficiency Defect in 17β-hydroxysteroid dehydrogenase Aromatase deficiency CYP 19 (15q21.1) In utero exposure to androgens or progestational agents Undervirilized male Androgen insensitivity (complete, partial, mild) Disorders of testosterone biosynthesis Lipoid adrenal hyperplasia Defect in 17α-hydroxylase/lyase Defect in 17β-hydroxysteroid dehydrogenase 5α-Reductase 2 deficiency Leydig cell hypoplasia Smith-Lemli-Opitz syndrome Persistent müllerian duct syndrome Type 1 Type 2 Embryopathy Penoscrotal transposition Penile agenesis Hypospadias Bladder and cloacal exstrophy Rokitansky-Kuster-Hauser syndrome Müllerian aplasia Miscellaneous syndromes associated with genital ambiguity
SRY (Yp11.3) SOX1 (17q24.3-q25.1) SF1 (9q33) WT1 (11p13) DAX-1 (Xp21.3-p21.2) Dhh (12q13.1)
CYP 21 (6p21.3) CYP 11B1 (8q24.3) HSD3B2 (1p13.1) 17 β-HSD3 (9q22)
AR (Xq11-12) StAR (8p11.2), CYP 11A (P450scc) CYP 17 (10q24.3) 17 β-HSD3 (9q22) SRD5A2 (2p33) LCGR (2p21) DHCR7 (11q12-q13) MIS/AMH (19p12.3-p13.2) MIS/AMHR2 (12q13)
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formation or impaired differentiation of an undifferentiated gonad to a testis imparts an increased risk for malignant transformation. Therefore, management usually includes gonadectomy and replacement of estrogens or androgens at the time of puberty to induce secondary sexual maturation (details provided in Chapter 6). Ovarian dysgenesis from haploinsufficiency of the X chromosomes, however, is not associated with an increased risk for malignancy; thus, gonadal exploration is usually unnecessary. The extent of genital virilization generally correlates with gonadal histology and is useful as a parameter of androgen exposure in the decision regarding gender assignment. More so than for the other intersex categories, sex assignment also considers the appearance and function of the external genitalia. Complete or Partial Gonadal Dysgenesis
In children with complete gonadal dysgenesis, the gonads never differentiate and regress to form streaks (46,XY sex reversal). The somatic cells in the streak gonads remain undifferentiated and are unable to produce testosterone or MIS; thus, the internal and external genitalia develop along the inherently female pathway, sometimes with subtle evidence of minor virilization. If the genitalia are female in appearance, a discrepancy between the prenatal cytogenetic analysis and phenotype may lead to early diagnosis; otherwise, the condition may remain unrecognized until the failure of puberty occurs. At that time, primary gonadal failure (elevated FSH and LH) in a patient with eunuchoid body proportions, normal stature, a small uterus with nonvisualized ovaries, and a 46,XY karyotype suggest the diagnosis. If the karyotype is 46,XX or unknown, the differential diagnosis of primary gonadal failure at puberty also includes autoimmune ovarian failure, Turner syndrome, or, rarely, an FSH receptor gene defect. In patients with gonadal dysgenesis, the elevated gonadotropins at puberty occasionally stimulate the residual nests of hilar cells sufficiently to produce testosterone and cause clitoromegaly and hirsutism. In the partial or incomplete form, the gonads are dysgenetic rather than streaks. The phenotype can range from mild clitoromegaly and posterior labial fusion to more obvious genital ambiguity. Development of the müllerian structures is variable and can be discordant between the two sides, depending on the extent of Sertoli cell function in each gonad. Gender assignment is usually female. Virilization may occur at puberty if the gonads are not removed. The risk for gonadoblastomas (seminomas and dysgerminomas) in individuals with gonadal dysgenesis is 10% to 30%. Spontaneous estrogen effects such as breast development or virilization may be the initial manifestation.
Gonadal mosaicism is the most frequently identified cause of gonadal dysgenesis. Defects in genes that are essential for gonadal differentiation and testis determination, such as SRY, SOX9, and WT1 (the Wilms’ tumor suppressor gene), and gene duplications of DAX-1 or WNT4 have also been implicated in gonadal dysgenesis. In the majority of patients with gonadal dysgenesis, however, no genetic defects have been found, suggesting the possibility of mutations in unidentified genes in the testicular determination pathway. Mixed Gonadal Dysgenesis
Children with mixed gonadal dysgenesis have asymmetrical gonadal histology, typically with a streak gonad and a contralateral dysgenetic or normal testis. In the dysgenetic gonad, Sertoli cell secretion of MIS is usually better preserved than Leydig cell production of testosterone. The phenotype can be male, ambiguous, or female in appearance with variable and often asymmetrical rudimentary müllerian structures. A hemiuterus and fallopian tube are often present on the side of the streak gonad. If one gonad is a normal testis, testosterone secretion may be adequate for full virilization of the external genitalia and secondary sexual maturation, in which case the diagnosis may be difficult to detect. The incidence of gonadoblastoma in dysgenetic testes is 20%, of which one third are germ cell tumors. Carcinoma in situ is even more common. When gender assignment is male, early gonadal biopsy is necessary to determine the nature of the testicular tissue and direct further management. If the biopsy reveals normal testicular histology and endocrine function is intact with normal androgens and gonadotropins, the testis can be left in place. Close monitoring with annual imaging studies (sonography, computed tomography, or magnetic resonance imaging) and a repeat biopsy at the onset of puberty and then again at 20 years of age are recommended. If carcinoma in situ is absent at these time points, malignant transformation of a histologically normal testis is less likely. Dysgenetic testes and streak gonads are removed early because of their increased malignant potential. The karyotype associated with this condition is 45,X/46,XY. Prenatal cytogenetics has revealed a higher than expected incidence (1.7:10,000) of this karyotype. The majority (90%-95%) were associated with normal male external genitalia, although an autopsy series found ovotestes in 2 of 11 cases with normal male genitalia. This karyotype can also be associated with a Turner syndrome phenotype. True Hermaphroditism
True hermaphroditism is a rare intersex condition in which an individual has both testicular and ovarian tissue.
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The largest numbers of cases have been reported from Africa and Europe. Children with this disorder have ambiguous genitalia ranging from a female phenotype with slight clitoromegaly to a minimally undervirilized male phenotype. More commonly, the genitalia are clearly ambiguous with microphallus (with or without chordae), hypospadias (commonly penoscrotal or perineoscrotal), fused labioscrotal folds, and cryptorchidism. Müllerian structures develop on the side with an ovary, whereas müllerian structures are absent and a vas deferens and an epididymis may be present on the side with a testis. When the gonad is an ovotestis, there is partial müllerian regression and wölffian duct differentiation. Some cases are diagnosed at puberty with the development of discordant secondary sexual characteristics. Males may present with prominent gynecomastia or cyclical penile bleeding and females may present with virilization and amenorrhea. Possible gonadal combinations include an ovotestis with an ovary (50%), bilateral ovotestes (30%), and an ovary and a testis (20%). The most frequent gonad is an ovotestis, followed by an ovary, then a testis. Ovaries are more likely to be located on the left side (76.5%), whereas ovotestes or testes are more common on the right (60.3%). This distribution may be due to the effect of asymmetric gonadal growth on gonadal differentiation. Ovaries remain intraabdominal, whereas gonads containing testicular tissue may lie within the abdomen or undergo varying degrees of descent, depending on the extent of testicular tissue in the gonad. Thus, an ovotestis may be abdominal (50%), inguinal (26%), or labioscrotal (24%) in position. In an ovotestis, the firm, pale, convoluted appearing ovarian tissue can be clearly demarcated from the smooth yellow testicular tissue. On ultrasonography, testicular tissue appears fine and granular with a homogeneous echogenicity, whereas an ovary is hypoechoic with identifiable follicles. The diagnosis of true hermaphroditism requires the presence of functional ovarian and testicular tissue containing ovarian follicles and distinct seminiferous tubules, respectively. The testicular tissue is often immature and dysgenetic, however, the estimated risk for malignant transformation is 5%, less than that observed with complete or partial gonadal dysgenesis. Interstitial and peritubular fibrosis, hyalinization of the basement membranes of tubules, tubular atrophy, and hyperplastic Sertoli cells have been described. Complete spermatogenesis producing functional sperm is rare. Ovarian tissue, on the other hand, is generally normal, even in an ovotestis. Primordial follicles are present before puberty and follicles develop to various stages in the mature ovary. Ovulation and pregnancy are possible. When the gender assignment is female, an ovary is left in place, but testes and ovotestes are resected to avoid virilization at puberty. Occasionally only the testicular part of an
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ovotestis is excised, while the ovarian tissue is retained in situ to preserve ovarian function and fertility. When the gender assignment is male, a histologically normal testes can be left in place but the contralateral ovary or ovotestes is usually resected. The karyotype can be 46,XX (70%), mosaic (20%), or 46,XY (10%). If dysgenetic gonads are present, a Y chromosome complement is likely to be found. Almost all (99%) of patients of African or mixed African origin have a 46,XX karyotype, whereas 40% of European patients have sex chromosome mosaicism. True hermaphroditism and gonadal dysgenesis have been found within the same pedigree. Postulated causes of true hermaphroditism include germline SRY mutations, selective activation of testicular differentiation in part of the gonad, asymmetrical gonadal growth and differentiation, and chimerism of 46,XX and 46,XY embryos. Congenital Anorchia or the Vanishing Testes Syndrome
Congenital anorchia overlaps the spectrum of gonadal dysgenesis but is attributed to loss of the testes or gonads secondary to vascular insult rather than a molecular defect in gonadal formation. The karyotype is therefore 46,XY and the extent of virilization depends on the developmental stage at which testicular function is lost (see Figure 7-2). Deficient androgen secretion before 8 weeks’ gestation leads to a female internal and external phenotype that includes differentiated müllerian structures. If the loss of function occurs during the critical period for male differentiation from 8 to 10 weeks’ gestation, the genitalia are ambiguous, with variable development of the wölffian and müllerian ducts. If the vascular insult and testicular loss occur after 12 to 14 weeks’ gestational age, although the internal and external genitalia are male in appearance and the müllerian structures are absent, virilization is incomplete. The deficiency of androgens during the second and third semesters may lead to hypospadias and failure of the phallus to increase in size.
Virilization in a Genetic Female (Female Pseudohermaphroditism) Virilization of the genitalia in a child with a 46,XX karyotype and normally differentiated ovaries is typically due to nongonadal androgens, most commonly from the fetal adrenal (see Table 7-1). Rarely, the androgens are of placental or maternal origin. The excess androgens do not disrupt müllerian duct development; therefore, the uterus and fallopian tubes are normally formed. The timing and extent of androgen exposure during the critical stages of sex differentiation dictate the magnitude of the masculinizing effects. Early exposure to androgens can fully virilize the external
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genitalia, whereas late exposure may cause only clitoromegaly. Management involves treatment of the primary condition to avoid ongoing androgen exposure. Because the ovaries are usually functional, hormonal therapy is seldom needed for secondary sexual maturation at puberty unless the gender of rearing is male. Severe virilization may require urogenital reconstruction. Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH), a condition caused by autosomal recessive enzymatic defects in cortisol biosynthesis, is by far the most common cause of virilization in genetic females (Figure 7-6). In the predominant virilizing forms of CAH, 21α-hydroxylase and 11β-hydroxylase deficiencies, the affected enzyme is necessary for synthesis of cortisol and aldosterone but not for androgens. The compensatory rise in corticotropin releasing hormone (CRH) and corticotropin (ACTH) in response to inadequate serum cortisol stimulates adrenal steroidogenesis and causes adrenal hyperplasia. Consequently, adrenal androgens and the steroid precursors proximal to the enzymatic defect accumulate, contributing to the clinical manifestations of this condition. The management of virilization secondary to cortisol biosynthetic defects consists of providing sufficient glucocorticoids to suppress the ACTH drive to prevent stimulation of adrenal steroidogenesis.
21a-Hydroxylase Deficiency (P450c21)
Mutations or deletions of the CYP21 gene (6p21.3) account for over 90% of cases of CAH, with an incidence of 1 in 14,000 live births and a carrier frequency of 1 in 60. Both male and female infants have hyperpigmentation due to high ACTH levels, and subtle symptoms of adrenal insufficiency such as feeding intolerance and irritability are present early. The extent of virilization of female infants depends on the severity of the enzymatic defect (Figure 7-7). Although adrenal androgens are already elevated during the initial stages of sex differentiation at 8 to 10 weeks, complete masculinization of the external genitalia is rare. An enlarged phallus with the urethral opening on the shaft or at the base of the phallus and fused wellrugated labioscrotal folds are more common. The genitalia of affected males are imperceptibly affected; therefore, if newborn screening is unavailable, males present at 1 to 2 weeks of age in an acute adrenal crisis with emesis, hyponatremic dehydration, and hyperkalemia. Milder cases of CAH are sometimes missed at birth and present in early childhood with pubic hair, clitoromegaly or phallic growth, and accelerated linear growth. About 70% of infants with 21α-hydroxylase deficiency have significant salt wasting, which can cause rapid metabolic decompensation, lending urgency to the rapid diagnosis of infants with intersex conditions. Marked elevations of
Cholesterol
CYP 11A
CYP 17
Pregnenolone Figure 7-6 Sex Steroid Biosynthetic Pathway. The enzymatic steps necessary for the biosynthesis of aldosterone, cortisol, testosterone, and estradiol. Mutations in enzymes that impair cortisol synthesis lead to compensatory adrenal hyperplasia and signs of glucocorticoid deficiency, whereas mutations affecting only sex steroid production have minimal systemic symptoms.
3 βHSD
CYP 17 17-OH-Pregnenolone
CYP 17
Progesterone
DHEA CYP 17
Androstenedione
17-OH-Progesterone
CYP 11 β2 Corticosterone CYP 11 β2
Estrone
17 β HSD
CYP 21 11-deoxycorticosterone
CYP 19
Testosterone
11 deoxycortisol
CYP 19
CYP 11 β1
Dihydrotestosterone
Cortisol
5 α-reductase 2
18 OH corticosterone CYP 11 β2 Aldosterone CYP 11 β2 (11β hydroxylase, 18 hydroxylase, 18 oxidase) CYP 17 (17α hydroxylase, 17,20 lyase) CYP 19 (aromatase)
Estradiol
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Female
Bladder Müllerian duct Müllerian tubercle Primitive urethra
Undifferentiated stage Vaginal plate
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Male
Vaginal plate
Prostatic utricle
Uterus Vagina Normal
1
2
3
4
5
Normal
Perineal urethra
Cross-sectional view
A
Female Glans Urethral fold
Indifferent Urethral groove
Genital tubercle
Genital fold
Glans Urethral groove
Genital swelling
Anus
Labial swelling
Male
Scrotal swelling
Clitoris Labia minora
Urethral orifice
Labia majora
Vaginal opening
Prepuce Scrotal raphe Normal
B
1
2
3
4
5
Urethral orifice
Scrotum
Normal
External view Figure 7-7 Virilization of the Urogenital Sinus and Genitalia in 46,XX Patients with Congenital Adrenal Hyperplasia. The varying degrees of virilization of the urogenital sinus and genitalia are depicted in the cross-sectional (A) and external (B) views and staged as proposed by Andrea Prader. Normal female and male sex differentiation are shown for comparison. (Redrawn with permission from White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Endocr Rev 2000;21:245.)
17-hydroxyprogesterone, androstenedione, and testosterone are pathognomonic. In infants with adrenal crisis, vigorous volume expansion with isotonic saline, followed by rehydration with 5% to 10% dextrose and 0.45% normal saline, and stress doses of intravenous steroids, rapidly stabilizes the clinical status. Glucocorticoid and mineralocorticoid replacement decreases androgen production by suppressing ACTH secretion and halts further virilization in infants and children. Clitoromegaly becomes less obvious over time as the
labia majora and minora grow in size. Steroids are gradually tapered to physiological replacement doses of oral hydrocortisone (10-15 mg/m2/day) in two or three divided doses. Fludrocortisone at a dosage of 0.05 to 0.2 mg/day is necessary in all children with salt-wasting forms of CAH (low sodium, high potassium, and high renin levels). Aldosterone deficiency can be subclinical in children with a diagnosis of simple virilizing CAH; thus, the addition of fludrocortisone may improve metabolic control and permit lower doses of hydrocortisone.
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Other Virilizing Forms of Congenital Adrenal Hyperplasia
11b-Hydroxylase Deficiency 11β-hydroxylase deficiency, the second most common cause of CAH, has an incidence of 1 in 100,000. The clinical features of infants with defects in the CYP11B1 gene (8q24.3) are similar to those with 21α-hydroxylase deficiency except for the development of low renin hypertension at older ages. The biochemical findings of elevated ACTH, 17-hydroxyprogesterone, androstenedione, and testosterone also overlap, but 11-deoxycortisol and 11-deoxycorticosterone are disproportionately elevated in this disorder. At high concentrations, 11-deoxycorticosterone binds to the mineralocorticoid receptor and causes hypertension. 3b-Hydroxysteroid Dehydrogenase Deficiency Defects in the HSD3B2 gene (1p13.1) result in deficiency of 3β-hydroxysteroid dehydrogenase (3β-HSD), an enzyme necessary for synthesis of cortisol, aldosterone, and sex steroids. This disorder is associated with mild virilization in affected females due to peripheral conversion of the elevated dehydroepiandrosterone (DHEA) to androgens. In contrast to 21-hydroxylase and 11-hydroxylase deficiencies, 3β-HSD deficiency affects testosterone synthesis; therefore, males are undervirilized. Elevated DHEA, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxypregnenolone and a markedly increased ratio of 17-hydroxypregnenolone to 17hydroxyprogesterone are diagnostic.
Undervirilization in a Genetic Male (Male Pseudohermaphroditism) Male sex differentiation is a complex process that depends on the active secretion and interaction of two testicular hormones and the responsiveness of their target tissues; consequently, the differential diagnosis of undervirilization in genetic males encompasses a heterogeneous group of disorders. Any perturbation in androgen action during the period of sex differentiation or phallic enlargement can impair genital virilization in a child with a 46,XY karyotype and normally formed testes. The timing and extent of androgen exposure and action are both critical for complete masculinization of the internal and external genitalia. In most cases of genital ambiguity due to inadequate virilization in genetic males, only the androgen pathway is affected; MIS expression and induction of müllerian duct regression is intact. Müllerian remnants may persist, however, because androgens are needed to potentiate MIS action for complete involution of the müllerian ducts. In evaluating an undervirilized genetic male, several clinical points are important to keep in mind: (1) the severity of the genital ambiguity can vary within a single diagnosis, (2) the clinical phenotype is often indistinguishable among different etiologies for the genital ambiguity, and (3) the diagnostic evaluation is frequently inconclusive without identification of a specific etiological condition (Table 7-1).
Aromatase Deficiency
Aromatase deficiency (CYP19 gene, 15q21.1) is a rare autosomal recessive cause of virilization in 46,XX individuals. Aromatase converts in utero fetal and maternal adrenal androgens to estrogens; a deficiency of either placental or fetal aromatase activity causes elevated circulating androgens and severe virilization of the fetal genitalia. With placental aromatase deficiency, the mother also becomes progressively virilized during the pregnancy. In Utero Exposure to Androgens or Progestational Agents
A less common cause of virilization in a 46,XX infant is in utero exposure to androgens of nonfetal origin. No medical therapy is necessary for the infant, as removal from the intrauterine milieu eliminates the source of the androgens. Maternal use of androgens or drugs with androgenic potency such as progestational agents or some anticonvulsants has been implicated in fetal virilization. Maternal and fetal virilization can also be caused by arrhenoblastomas and other rare androgen-secreting ovarian and adrenal tumors. The minor elevations in testosterone associated with hyperthecosis or polycystic ovarian syndrome seldom cause fetal virilization because of efficient placental aromatization of androgens to estrogens.
Defects in Testosterone Biosynthesis
An enzymatic defect in any of the enzymes required for testosterone biosynthesis can attenuate testosterone production and compromise full virilization of the genitalia. Some of these enzymatic defects also disrupt cortisol synthesis and cause CAH, whereas others are specific to the testosterone pathway (see Figure 7-6). The disorders associated with a defect in the cortisol biosynthetic pathway are treated by replacement of glucocorticoids and mineralocorticoids (discussed earlier). Among the conditions that cause inadequate virilization, sex steroids are necessary at puberty for secondary sexual maturation in all cases. Congenital lipoid adrenal hyperplasia is a rare disorder that results from a mutation in the gene coding for steroidogenic acute regulatory protein (StAR) (8p11.2). Formerly attributed to a deficiency of the side chain cleavage enzyme (P450scc), only one family has been identified with a mutation in this gene; most patients who have been studied have loss of function mutations or deletions of StAR. The loss of StAR activity results in the inability of cholesterol to be transported from the outer to the inner mitochondrial membrane, an essential step for the acute, stimulated synthesis of all gonadal and adrenal steroids.
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Consequently, cholesterol lipids accumulate in steroidogenic cells of the adrenal cortex and the gonads and further damage these cells, hindering basal synthesis of steroids as well. Affected males are severely undervirilized to the extent that the external genitalia may appear female or only minimally ambiguous, the wölffian structures are hypoplastic, and the testes are undescended. The vagina ends in a blind pouch because the müllerian ducts regress normally. Affected females have normal genitalia so the condition may not be recognized at birth. If undiagnosed, severe acute adrenal insufficiency causes rapid metabolic decompensation, and early death is not uncommon. ACTH is elevated, but all steroids and steroid precursors are low. Full steroid replacement with both glucocorticoids and mineralocorticoids is necessary for this and the following two disorders. Because of the female-appearing genitalia, 46,XY males with this condition usually undergo orchiectomy and are reared as females. At puberty, estrogen is given for breast development and lowdose testosterone can be used to promote growth of pubic and axillary hair. 3b-Hydroxysteroid dehydrogenase deficiency (HSD3B2) is associated with male undervirilization; the phallus is typically small with incomplete scrotal fusion and hypospadias. Affected 46,XX females are partially virilized. The defect in this enzyme compromises testosterone production with resultant low serum testosterone. DHEA is elevated and can be converted peripherally to androgens to cause virilization of affected patients. 17-hydroxypregnenolone is elevated, thereby increasing the ratio of 17hydroxypregnenolone to 17-hydroxyprogesterone. 17a-Hydroxylase/lyase deficiency due to a mutation in the CYP17 gene (10q24.3) affects conversion of 17hydroxypregnenolone to DHEA, a precursor in the sex steroid pathway. The decreased production of testosterone causes genital ambiguity in genetic males. Although 17αhydroxylase/lyase is also necessary for cortisol and aldosterone production, adrenal insufficiency is often subclinical due to elevated precursor steroids. At high concentrations, corticosterone has glucocorticoid activity and 11-deoxycorticosterone has mineralocorticoid activity. Moreover, the enzymatic properties of this bifunctional enzyme can be differentially affected and are modulated by cofactors. 17b-Hydroxysteroid dehydrogenase deficiency is an autosomal recessive condition caused by mutations in the 17b-HSD3 gene (9q22). The conversion of androstenedione to testosterone is impaired, leading to ambiguous or female genitalia. Considerable virilization may occur at puberty from peripheral conversion of androstenedione to testosterone. A milder late-onset form presents with pubertal gynecomastia in an adolescent with a normal male phe-
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notype. An abnormally high ratio of androstenedione to testosterone in response to hCG stimulation is diagnostic. In an affected female, the elevated DHEA and androstenedione can be metabolized to an active androgen to cause significant virilization. 5a-Reductase-2 deficiency, also referred to as pseudovaginal perineal-scrotal hypospadias, is an autosomal recessive disorder caused by mutations of the SRD5A2 gene (2p23). This enzyme reduces testosterone to its more active metabolite, dihydrotestosterone (DHT), at target tissues. DHT is required for male sex differentiation of the external genitalia and for growth of facial hair. In this disorder, the external genitalia are ambiguous (perineoscrotal hypospadias and microphallus), a urogenital sinus and pseudovagina are generally present, and spermatogenesis is impaired in the cryptorchid testes. Development of the internal structures is unaffected because DHT is not required: the wölffian ducts differentiate fully in response to testosterone and the müllerian ducts undergo normal regression. The external genitalia become virilized during puberty and fertility is possible. An elevated ratio of testosterone to DHT (T/DHT) is diagnostic. In prepubertal children, the basal ratio may be normal, but the hCG-stimulated ratio should increase. DHT values are between 5 and 60 ng/dL at birth in males and then decrease rapidly in the first week of life. From 30 to 60 days, DHT increases transiently to 12 to 85 ng/dL and then decreases a few months later to the prepubertal range (90%) are point mutations. The same point mutation may have variable expression within a family pedigree. This has been attributed to genetic background factors such as coregulatory proteins or to somatic mosaicism. The effect of mutations in different domains of the androgen receptor on androgen binding and signaling, however, has been well characterized. The first of the eight exons encodes the N-terminal fragment and has a role in transcriptional activation. Nearly all mutations in exon 1 cause premature termination of translation and CAIS. This region has two homopolymeric amino acid repeats that are polymorphic in size: polyglutamine (9-36 repeats) and polyglycine (10-31 repeats). Kennedy syndrome, a motor neuropathy associated with MAIS, results from expansion of the polyglutamine tract beyond 38 repeats. Mutations of exons 2 and 3, the receptor DNA binding domain (composed of two zinc-containing fingers), interfere with DNA binding but androgen binding is preserved. Exons 5 to 8, the most frequent site for missense mutations, encode the ligand binding domain. These mutations either completely
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disrupt androgen binding or alter binding affinity such that higher concentrations of androgens are necessary for receptor activation. A small hinge region between the DNA and ligand binding domains may be important for receptor activation. Persistent Müllerian Duct Syndrome The persistent müllerian duct syndrome (PMDS) is an autosomal recessive disorder characterized by well-developed müllerian duct derivatives in 46,XY males with cryptorchid testes and otherwise normal male internal and external genitalia. Because the external genitalia are fully virilized, this condition is a variant of normal development and not usually considered an intersex condition. Transverse testicular ectopia in a child with unilateral cryptorchidism and an inguinal hernia is a common presentation of PMDS (80%). The uterus, fallopian tubes, and both testes are found in a hernial sac. Alternatively, PMDS can present as bilateral cryptorchidism with the uterus and tubes in the abdomen and intra-abdominal testes in the round or broad ligaments. The testes are hypermobile and have an increased risk of torsion and malignant changes. Fertility appears to be reduced because of inadequate communication of the testes with male excretory ducts, complications of orchiopexy, or the cryptorchid state. The diagnosis generally arises during an evaluation for cryptorchidism or when müllerian structures are observed during abdominal or pelvic surgery. Serum MIS is undetectable or low in cases caused by gene defects but normal with receptor defects. However, an undetectable MIS in a child with bilateral cryptorchidism is also consistent with anorchia or vanishing testes. The diagnosis of PMDS can be made by performing an hCG stimulation test. A normal rise in testosterone is consistent with PMDS, and an absent response is predictive of anorchia. A sonogram of the pelvis to identify müllerian structures is also helpful. Early orchidopexy should be performed to optimize testicular function. The fallopian tubes and uterus are excised carefully to avoid compromising blood supply to the testes and damaging the vas deferens, which is usually embedded in the lateral uterine wall and cervix. Almost 50% of patients with PMDS have mutations in the MIS gene (19p), most commonly in exons 1 and 5. Another 40% have mutations in the gene for the MIS receptor; 50% of these have a common 27-bp deletion in exon 10. Up to 15% of patients with PMDS have no discernible mutations in the coding sequences for either the MIS gene or receptor. Gonadotropin, Growth Hormone, or Human Chorionic Gonadotropin Deficiency
Gonadotropin deficiency and placental insufficiency have both been associated with cryptorchidism and
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microphallus. During sex differentiation, testosterone synthesis is initially gonadotropin independent; thus, midline fusion and differentiation of the genitalia proceed normally. By the second trimester, testosterone secretion by the Leydig cells is probably regulated by LH or hCG. A deficiency in either hormone leads to inadequate production of androgens during the period of penile growth and may manifest as microphallus. A similar phenotype is seen with GH deficiency as GH potentiates the effects of androgens on phallic growth. Miscellaneous Causes of Undervirilization
The Smith-Lemli-Opitz syndrome due to a mutation of the sterol-Δ7-reductase gene (11q12-q13) leads to failure to thrive, genital ambiguity, and congenital abnormalities in brain, heart, lung, and kidney development. The genital ambiguity may be severe or present as isolated hypospadias. This enzyme is necessary for the synthesis of cholesterol, a precursor for all steroid hormone production, including androgens. A deficiency of this enzyme leads to low steroids and increased 7-dehydro-cholesterol, the immediate precursor to cholesterol.
Congenital Embryopathy Anomalies of urogenital development that are independent of the karyotype and gonadal hormone action may occur during embryogenesis, frequently in association with other congenital anomalies. In these cases, the gonads are concordant with the karyotype. Examples are penoscrotal transposition, penile agenesis with imperforate anus, bifid phallus with bladder extrophy, and vaginal anomalies. The 46,XX infants are typically raised as females, whereas sex assignment in 46,XY infants traditionally depended on genital anatomy and the potential for function after corrective surgery. However, an equally important consideration in this decision may be the influence of fetal androgens on gender identity, as demonstrated by recent case reports of 46,XY infants with cloacal extrophy who were raised as girls but desired sex reassignment at adolescence. The appropriate sex assignment of infants in this category is being readdressed and is an area of much controversy and debate. Hypospadias occurs if fusion of the penile urethra is incomplete. This is one of the most common congenital anomalies, occurring in 4 to 8 of 1000 liveborn male infants. First-degree hypospadias with the urethral opening on the glans penis is not usually associated with other urogenital anomalies and seldom requires extensive evaluation or correction. More severe forms with the urethral opening along the shaft or the base of the penis or on the perineum warrant investigation for underlying intersex conditions, particularly if associated anomalies are present. Although
most cases are multifactorial in origin, mild PAIS and sex chromosome abnormalities can present as isolated hypospadias. Maternal intake of progestational agents, maternal cocaine use, and exposure to environmental estrogens and antiandrogens have all been implicated. Both vaginal atresia and müllerian aplasia (RokitanskyKuster-Hauser syndrome) present as primary amenorrhea in adolescents with normal breast and pubic hair development. The karyotype is 46,XX, and hormonal profiles are normal with intact ovaries. These developmental defects may be familial. Specific gene defects are starting to be identified, such as one family with müllerian aplasia due to a defect in the gene for hepatic transcription factor 2.
EVALUATION Any divergence in development of the external genitalia from the norm may indicate an intersex condition. The diagnosis of an intersex condition is unequivocal in an infant with a phallus intermediate in length between normal standards for a clitoris and penis (6.4 mm to 2.2 cm at birth), incomplete fusion of the labioscrotal folds, an aberrantly located urethral opening, and nonpalpable gonads. The finding of an abnormal phallic size or labioscrotal fusion alone is considered a genital anomaly associated with an underlying intersex condition, but cryptorchidism or hypospadias may be isolated findings without such association. On the other hand, intersex conditions may also present without any genital ambiguity as exemplified by children with CAIS or pure gonadal dysgenesis. The finding of ambiguous genitalia in a newborn is psychologically stressful for the family and requires prompt attention by an experienced team that includes an endocrinologist, an urologist or a pediatric surgeon, a child psychiatrist or psychologist, and the family’s pediatrician. Involvement of clergy and introduction to support groups or other families with similar issues are helpful for emotional support. Parents should be shown the genitalia of their baby and reassured that although the genitalia are incompletely formed or overly developed, the condition occurs as part of a developmental process, similar to other more common congenital anomalies. Parents should be made aware of the difficulty in determining the appropriate sex assignment for their infant until the evaluation is complete and kept fully informed of the progress of the diagnostic work-up. A systematic and thorough evaluation using a multidisciplinary approach to diagnosis and management is essential. Although most conditions are not medically urgent, timely recognition of a common cause of genital ambiguity, salt-wasting CAH, circumvents lifethreatening decompensation.
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History and Examination The evaluation starts with a detailed history that should include exposure to androgenic and progestational agents in intrauterine life, maternal virilizing symptoms, and family history of ambiguous genitalia, unexplained infant deaths, primary amenorrhea, infertility, and inguinal hernias with prolapsed gonads. The physical examination should focus on identifying syndromic features, determining the position of the gonads, and establishing the genital anatomy. Asymmetrical positioning of the gonads is suggestive of asymmetrical development of the gonads as seen with disorders in gonadal morphogenesis. Any gonad palpated below the external inguinal ring is presumed to contain testicular tissue; ovarian tissue without any testicular components rarely descends below the inguinal ring. For example, infants with true hermaphroditism may have an abdominal ovary and a testis or an ovotestis in the scrotum or labial folds. The size of the phallus, position of the urethral opening, extent of chordae, and development of the labioscrotal folds are noted. The uterus, when present, is sometimes palpable on gentle rectal examination as a firm, midline, pencil-sized structure. Genital pigmentation may be due to hypersecretion of ACTH associated with CAH.
Laboratory Studies Cytogenetic analysis with high-resolution banding should be performed in all infants and children with ambiguous genitalia. The sex chromosomes can be specifically examined by fluorescent in situ hybridization (FISH) using centromeric probes for the X chromosome and centromeric or
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long arm probes for the Y chromosome. FISH for SRY may be helpful in patients with sex reversal. Molecular studies are also available in research laboratories to identify genetic mutations in many of the genes involved in sex differentiation. This includes, but is not limited to, SOX 9, DAX-1, and SF-1 genes in the steroidogenic pathway for cortisol and testosterone biosynthesis, MIS and its receptor, 5α-reductase, and the receptors for androgens and LH (see Table 7-1). If CAH is a possibility, electrolytes should be followed closely, and 17-hydoxyprogesterone and other adrenal precursors are measured to delineate specific enzymatic deficiencies. If the enzymatic defect is severe enough to cause genital abnormality, basal steroid values and ratios should be abnormal. Occasionally, measurement of adrenal steroid precursors after stimulation with 125 to 250 μg of ACTH is needed to confirm a diagnosis. The inclusion of 17-OHprogesterone in the newborn screen in most states allows early diagnosis of virilizing CAH infants who are not recognized clinically. The sexually dimorphic expression of MIS in prepubertal children makes it useful for identifying testicular tissue in children with intersex conditions. Unlike testosterone, MIS is produced only in the gonads. Serum MIS concentrations are high in prepubertal males and low in females, with no overlap in values before the age of 6 years (Figure 7-8). Although the range of values starts to overlap at this time, mean values in older children are still clearly distinguishable (43 ng/mL in boys and 2.7 ng/mL in girls). Consequently, in young boys, an MIS value within the male range is predictive of testicular tissue. Conversely, except for rare cases of PMDS, an undetectable MIS value is highly predictive for absent testicular tissue. Moreover, MIS values
1000 Upper limit M Mean M
100 MIS (ng/ml)
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Figure 7-8 Serum Müllerian Inhibiting Substance (MIS) Values in Males and Females (Solid Black Line) and Girls (Broken Black Line). Serum MIS values are easily
Upper limit F 10
distinguishable in the prepubertal years between males and females with no overlap in values within the first few years of life. In contrast to testosterone, which is also secreted by the adrenal, MIS is a gonad-specific hormone.
Lower limit M 1
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correlate with the extent of parenchymal tissue and may be helpful for distinguishing among different intersex diagnoses. A low MIS value is suggestive of a dysgenetic or hypoplastic testicular tissue associated with a disorder of morphogenesis. An MIS value in the normal or elevated male range is consistent with a structurally intact testis as seen in disorders of testosterone biosynthesis or androgen insensitivity. Assessment of testosterone is valuable for determining the etiology of an undervirilized genetic male but may not help with initial differential diagnosis. Serum testosterone concentrations in 46,XX girls with CAH can be elevated to a range that is indistinguishable from that of newborn males. In infants with disorders of morphogenesis, serum testosterone is quite variable: low with dysgenetic gonads and low or normal with ovotestes. In virilized genetic males, measurement of testosterone, DHT, and testosterone precursors helps identify testicular enzymatic defects or androgen insensitivity. Basal testosterone values adequately reflect androgen production only during early infancy when testosterone production transiently increases. At birth, testosterone values in males are elevated (75-400 ng/dL) but decrease within a few days to 20 to 50 ng/dL. From 4 to 12 weeks of life, testosterone levels rise to 100 to 400 ng/dL. By 6 months, testosterone declines to the prepubertal values of less than 10 ng/dL. In females, serum testosterone is lower at birth (20-65 ng/dL) than that of males and then decreases further during the first month to comparable prepubertal values of less than 10 ng/dL. During much of childhood, serum testosterone values are low and indistinguishable between males and females. With puberty, testosterone values gradually increase in males to the normal adult range of 300 to 1000 ng/dL and remain in the much lower range of 10 to 50 ng/dL in females. The low testosterone values during late infancy and childhood make it difficult to assess androgen biosynthetic capacity to differentiate between an ovary and testis. Stimulation with hCG is required for an adequate estimate of testicular function in the prepubertal testis. We administer hCG at a dosage of 1500 unit/m2 on days 1 and 3 and measure testosterone levels at baseline and on days 3 and 6. A doubling of testosterone values from baseline to day 3 and again from day 3 to day 6, with a peak testosterone greater than 50 ng/dL, is indicative of functional testicular tissue. A number of other protocols for hCG stimulation have been proposed, including a single dose of hCG, daily hCG administration for 5 days, or every other day for 1 week to 3 weeks; all serve to increase testosterone production. In prepubertal children, the Leydig cells are relatively refractory; thus, two injections of hCG may not sufficiently stimulate androgen production. A prolonged stimulation
test with administration of hCG every other day for 2 to 6 weeks may be needed to adequately assess the capacity for androgen synthesis. A robust rise in testosterone is observed with AIS and 5αreductase deficiency and a minimal increment is noted in testosterone biosynthetic defects or disorders of morphogenesis. No rise is observed with LH receptor defects or gonadal agenesis or in virilized genetic females. Androstenedione, DHEA, and DHT are also measured to assess sequential steps in the androgen pathway. The addition of gonadotropin measurements provides an index of the hypothalamic-pituitary-gonadal axis. Both LH and FSH are secreted in a pulsatile pattern; thus, basal values are usually of limited use unless elevated. At birth, LH abruptly rises almost 10-fold in male infants, stimulating a rise in testosterone in the first 3 hours of life. Within the first 24 hours, LH decreases to low values until 2 weeks of age, when it starts to rise transiently and peaks at 2 months. By 6 months, LH again declines to low prepubertal values. In male infants, the pulse amplitude of LH is much higher than that of FSH, resulting in stimulation of testosterone synthesis in the first few months. In female infants, the greater FSH pulse amplitude stimulates increased estrogen secretion during the first 2 to 3 years of age. During infancy and puberty, when the hypothalamicpituitary-gonadal axis is active, gonadotropins are responsive to negative feedback by sex steroids. As a result, FSH and LH increase when testosterone is deficient, whether due to an enzymatic defect or to absent or dysgenetic gonads. Elevated gonadotropins at these periods are therefore indicative of either absent gonads or deficient androgen action. During the remainder of childhood, however, gonadotropins are in a low prepubertal range and remain low even in children with gonadal dysgenesis or anorchia. Consequently, gonadotropins are helpful diagnostically when elevated but less useful if in the normal prepubertal range. The diagnostic work-up sometimes includes a short trial of depot testosterone to assess the response of the phallus to testosterone; this is particularly useful in infants with PAIS. Genital tissue biopsy for androgen receptor binding studies is helpful if AIS is suspected. In some cases, gonadal biopsy is necessary for diagnosis or to detect gonadoblastoma or carcinoma in situ. Laparoscopy may be needed to identify and remove dysgenetic testes.
Imaging Studies Imaging studies to define the internal genitalia are an essential aspect of the evaluation for an intersex condition. A pelvic ultrasound may be able to identify abdominal gonads and müllerian structures, especially in the hands of
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an experienced operator. Transrectal sonography is being used in some centers to improve resolution. Magnetic resonance imaging may better define the anatomy of the vagina, cervix, and müllerian structures and is more sensitive for localizing the gonads. However, both sonography and magnetic resonance imaging can miss small ectopic gonads. A retrograde genitogram helps delineate the anatomy of the urogenital sinus and the entry of the vagina and urethra. This is sometimes performed in conjunction with a cystoscopic examination.
MANAGEMENT OF AND TREATMENT OPTIONS FOR INTERSEX DISORDERS Classically, rapid sex assignment and early surgical correction to match the gender of rearing have been advocated. A key consideration in sex assignment was the potential for future sexual and reproductive function, keeping in mind the etiology, the anatomy of the genitalia, and the limitations of reconstructive surgery. This emphasis on genital anatomy and function was based on a fundamental assumption of gender neutrality in infancy, which has been questioned. The appearance of the external genitalia was also believed to affect the establishment of gender identity. Recent reports suggest that in utero androgen imprinting of the fetal brain may also be critical for establishing gender identity. Moreover, genetic and hormonal events during childhood and puberty may affect gender identity and adult sexuality. Therefore, fetal and postnatal virilization of the central nervous system has become an important additional consideration for sex assignment. Diamond and Sigmundson have recommended male sex assignment for 46,XY infants with mild PAIS, isolated hypospadias or microphallus, 5α-reductase or 17β-reductase deficiency, and severely virilized 46,XX infants with CAH. Female sex assignment is recommended for 46,XY infants with CAIS, severe PAIS, pure gonadal dysgenesis and less-virilized 46,XX infants with CAH. Sex assignment in conditions such as mixed gonadal dysgenesis and true hermaphroditism depends on the size of the phallus and the extent of labioscrotal fusion. The mean and the −2 SDs for stretched penile length are 3.8 and 3.0 cm for a male term infant and 3.0 and 2.3 cm for an infant born at 34 weeks, respectively. Standards are also available for very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. An extremely small phallus with minimal corporal tissue raises concerns about the phallic response to androgens and a comparable lack of fetal central nervous system virilization. Although these recommendations provide useful guidelines, many cases do not fit neatly into one of these categories, and each infant must be evaluated individually.
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After the diagnostic evaluation is complete, sex assignment should be made thoughtfully by consensus decision of the team, and discussed in depth with the family. When a child presents with ambiguous genitalia after early infancy, the previously assigned sex is usually supported. Sex reassignment is considered only when the gender identity of the child is discordant with the assigned sex. The timing of urogenital reconstructive surgery is highly controversial. The traditional approach advocates early surgical repair to enable concordance of the external genitalia with the gender of rearing. Clitoral recession, labioscrotal reduction, and vaginal exteriorization performed as a onestep procedure during infancy eliminates the trauma of repeated surgical procedures. In recent years, however, there has been a move toward delaying surgery because of limited long-term data on the psychological outcome of early versus late surgery and concerns regarding impairment of genital sensation. Proponents of this approach argue that urogenital reconstructive surgery is a cosmetic procedure that should be postponed until the child is able to provide informed consent. Moreover, some individuals with intersex conditions request sex reassignment as young adults, lending further credence to the need to reevaluate traditional approaches regarding urogenital reconstructive surgery. A compromise solution until long-term data is available is to assign sex early but to postpone surgery until a consensus is reached among the family members and medical care providers regarding the ultimate gender identity and role of the individual patient. If the assigned sex is male, a short course of testosterone can be given to promote phallic growth. Orchiopexy should be performed by 12 months of age to optimize testicular function and to facilitate monitoring for malignancies. Dysgenetic testes and ovotestes at increased risk of malignancy should be removed. Corrective surgery for hypospadias, chordae, or genital anomalies can be undertaken as a one-step procedure at 6 to 18 months of age but is not essential unless urinary function is compromised. Supplemental sex steroids are often necessary to induce puberty. Testosterone cypionate or enanthate at a dosage of 50 mg intramuscular monthly is begun at 12 to 14 years of age. The dose is increased by 25- to 50-mg increments every 6 to 12 months to achieve full masculinization over 3 years. Full replacement dose in adult males is 200 mg every 2 to 3 weeks. Testosterone can also be given via patch or cream (discussed in Chapter 6). Fertility is possible in men with secondary or tertiary gonadal insufficiency by treatment with pulsatile gonadotropin-releasing hormone or gonadotropins. When the assigned sex is female, removal of testicular tissue or dysgenetic gonads at risk for malignancy is recommended and urogenital reconstructive surgery may be needed. Hormone replacement is necessary to induce
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pubertal maturation. Low-dose estrogen replacement is initiated in girls at 11 to 12 years of age as 0.3 mg conjugated estrogens every other day or 50 to 100 ng ethinyl estradiol/kg/day. The dose of estrogen is increased gradually every 6 to 12 months to achieve complete pubertal maturation in 2 to 3 years, when cyclical progesterone is added. Estrogen can also be delivered via transdermal patches (discussed in Chapter 6). A regimen of 20 μg ethinyl estradiol or 0.625 mg conjugated estrogens daily, with 5 to 10 mg medroxyprogesterone acetate added on days 15 to 28, or a low-dose contraceptive with comparable hormone doses maintains feminization and should protect against osteoporosis and cardiovascular disease. Progesterone decreases the risk of endometrial dysplasia in those with an uterus but is unnecessary in individuals without a uterus.
CONCLUSION Despite major advances in the understanding of the pathophysiology of intersex conditions, the clinical management and long-term outcome of these complex conditions remain controversial and a focus of ongoing studies. Nevertheless, a comprehensive diagnostic evaluation and the involvement of an experienced multidisciplinary team are of utmost importance in the care of an infant or a child with an intersex condition. Although general principles and recommendations provide useful guidelines for the clinician, individual attention to the specific considerations for each child with one of these rare conditions facilitates his or her optimal management and helps ensure improved outcomes.
䉴
MAJOR POINTS
䉳
The embryo and gonad are initially undifferentiated. In male embryos, the induction of SRY initiates a transcriptional cascade of events that results in testis determination and consequent differentiation of the genitalia. In the absence of SRY expression, the gonad differentiates as an ovary and the genitalia are female in appearance. Specific molecular defects of genes in the sex determination pathway cause abnormalities in sexual differentiation, primarily by disrupting formation of the bipotential gonad or complete testis determination, and can be associated with syndromic conditions. In genetic males, the secretion of two hormones by the fetal testis is essential for normal male sexual differentiation of the internal and external genitalia. Müllerian inhibiting substance secreted by Sertoli cells induces regression of the müllerian ducts, the precursor of the female internal reproductive tract. Testosterone secreted by Leydig cells stimulates wölffian duct differentiation to form the male
䉴
MAJOR POINTS—Cont’d
䉳
reproductive tract. The testosterone is then converted to dihydrotestosterone to virilize the external genitalia. In a genetic female, the müllerian ducts differentiate into the fallopian tubes, uterus, cervix, and upper vagina in the absence of müllerian inhibiting substance, and the wölffian ducts regress in the absence of testosterone. Endogenous or exogenous androgen exposure can virilize a genetic female to varying extents depending on the timing and extent of androgen exposure. The most common cause of virilization in a genetic female is congenital adrenal hyperplasia caused by molecular defects in the gene for 21α-hydroxylase. The most common cause of undervirilization in a genetic male is androgen insensitivity caused by molecular defects in the androgen receptor gene. Asymmetry of gonadal position is often associated with a disorder of gonadal formation. Ovarian tissue generally does not descend below the external inguinal ring. Therefore, a gonad palpable below the external inguinal ring implies that testicular tissue is present and excludes the diagnostic category of “a virilized genetic female.” If müllerian structures are present, the differential diagnosis would include a disorder of gonadal morphogenesis, a virilized genetic female, or the persistent müllerian duct syndrome. If müllerian structures are absent, implying normal Sertoli cell function, undervirilization of a genetic male due to a disorder restricted to the androgen pathway is likely. This includes conditions such as androgen insensitivity, testosterone biosynthetic defects, and inactivating mutations of the luteinizing hormone receptor. Gender assignment and management can be a challenge and must be individualized for each patient. Management decisions should consider the etiology of the condition, appearance of the genitalia, potential androgen imprinting of the developing brain, ongoing effects of postnatal exposure to androgens, and psychosocial factors.
SUGGESTED READINGS Achermann JC, Meeks JJ, Jameson JL: Phenotypic spectrum of mutations in DAX-1 and SF-1, Mol Cell Endocrinol 2001; 185:17. Ahmed SF, Hughes IA: The genetics of male undermasculinization, Clin Endocrinol (Oxf ) 2002;56:1. Clarkson MJ, Harley VR: Sex with two SOX on: SRY and SOX9 in testis development, Trends Endocrinol Metab 2002;13:106. Diamond M, Sigmundson HK: Management of intersexuality: guidelines for dealing with persons with ambiguous genitalia, Arch Pediatr Adolesc Med 1997;151:1046. Grumbach MM, Conte FA: Disorders of sexual differentiation. In Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams’ Textbook of Endocrinology, 10th ed, Philadelphia, 2003, WB Saunders.
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Hughes IA: Mini-review: sex differentiation, Endocrinology 2001;142:3281.
Miller WL: Disorders of androgen biosynthesis, Semin Reprod Med 2002;20:205.
Kaye CI, Cunniff C, Frias JL, et al: Evaluation of the newborn with developmental anomalies of the external genitalia, Pediatrics 2000;106:138.
Muller J, Ritzen EM, Ivarsson SA, et al: Management of males with 45,X/46,XY gonadal dysgenesis, Horm Res 1999;52:11.
Koopman P: Sry, Sox9 and mammalian sex determination. In Scherer G, Schmid M, editors: Genes and Mechanism in Vertebrate Sex Determination, Basel, Switzerland, 2001, Birkhauser Verlag. Krob G, Braun A, Kuhnle U: True hermaphroditism: geographical distribution, clinical findings, chromosomes and gonadal histology, Eur J Pediatr 1994;153:2.
Quigley CA, De Bellis A, Marschke KB, et al: Androgen receptor defects: historical, clinical, and molecular perspectives, Endocr Rev 1995;16:271. Sarafoglou KS, Ostrer H: Familial sex reversal: a review, J Clin Endocrinol Metab 2000;85:483. Tilmann C, Capel B: Cellular and molecular pathways regulating mammalian sex determination, Recent Prog Horm Res 2002;57:1.
Lane AH, Lee MM: Mullerian inhibiting substance: a nontraditional marker of gonadal function, Curr Opin Endocrinol Diabetes 2001;8:296.
Tuladhar R, Davis PG, Batch J, et al: Establishment of a normal range of penile length in preterm infants, J Paediatr Child Health 1998;34:471.
Lerman SE, McAleer IM, Kaplan GW: Sex assignment in cases of ambiguous genitalia and its outcome, Urology 2000;55:8.
Warne GL, Zajac JD: Disorders of sexual differentiation, Endocrinol Metab Clin North Am 1998;27:945.
McPhaul MJ: Molecular defects of the androgen receptor, Recent Prog Horm Res 2002;57:181.
White PC, Speiser WP: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, Endocr Rev 2000;21:245.
Meyer-Bahlburg HFL: Gender and sexuality in classic congenital adrenal hyperplasia, Endocrinol Metab Clin North Am 2001;30:155.
Wilson JD: Androgens, androgen receptors, and male gender role behavior, Horm Behav 2001;40:358.
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CHAPTER
8
Introduction Normal Physiology The Growth Hormone Axis The Growth Plate
Growth Evaluation Phases of Normal Growth Prenatal Growth Growth During Infancy Growth During Childhood Growth During Puberty Measurement Growth Charts Distance and Velocity Standards Charts for Children With Growth Pathology Parental Target Height Skeletal Maturation and Prediction of Adult Height
Short Stature/Growth Failure The Clinical Problem Differential Diagnosis of Short Stature/Growth Failure Healthy but Short Children Nonorganic Etiologies Intrinsic Short Stature Systemic Diseases Endocrinopathies Initial Evaluation Evaluation by a Pediatric Endocrinologist Overall Approach to the Patient Treatment
Overgrowth Prenatal Onset of Overgrowth Postnatal Onset of Overgrowth Familial (Constitutional) Tall Stature Obesity Precocious Puberty Hyperthyroidism Genetic and Chromosomal Disorders Excessive Growth Hormone Secretion Diagnostic Evaluation of Tall Stature
Conclusion Major Points
Disorders of Growth ADDA GRIMBERG DIVA D. DE LEÓN
INTRODUCTION The scientific study of children’s growth and development began with the publication of the first textbook on growth, Wachstum der Menschen in die Lange by Johann Augustin Stoeller, more than 270 years ago (1729). This textbook did not contain any record of actual measurements; the first real growth study was reported a few years later in a doctoral thesis by Christian Friedrich Jampert. Jampert measured and recorded the height, weight, and other dimensions of a series of boys and girls at the Royal Orphanage of Berlin, completing the first cross-sectional growth study (1754). Count Philibert Guéneau de Montebeillard established the first longitudinal study of height when he recorded the heights of his son from birth to 18 years (1759-1777). This record has been extensively used and cited throughout the years. Until the end of the 19th century, pediatric textbooks included little on the subject of growth. It was the introduction of pediatric endocrinology as a specialty, and especially the recognition of growth hormone (GH) deficiency (GHD), that gave more impetus to the clinical study of growth.
NORMAL PHYSIOLOGY The Growth Hormone Axis GH (somatotropin), the principal mediator of somatic growth in childhood, acts within an axis of both positive stimuli and negative feedback loops (Figure 8-1). GH is synthesized and secreted by the somatotrophs, which comprise about half the cells of the anterior pituitary gland. The anterior pituitary communicates directly with the hypothalamus through a special fenestrated portal circulation, the exception to the blood-brain barrier. The hypothalamicpituitary unit is located at the base of the third ventricle, 127
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+ -
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Figure 8-1
The Growth Hormone (GH) Axis. GH release by the pituitary gland is controlled by the hypothalamic factors somatostatin (ss) and growth hormone–releasing hormone (GHRH). It is also stimulated by ghrelin, which is produced in the stomach. GH stimulates hepatic production of the circulating 150-kDa complex, composed of insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). IGF-I provides negative feedback control to both the pituitary and hypothalamus. Stimulatory signals are presented by solid arrows ; inhibitory, by dashed arrows.
allowing regulation by higher brain centers both through multiple afferent neural connections and through chemical agents from the cerebrospinal fluid. Afferent signals from the brain and hypothalamus regulate the pulsatile GH secretion, which achieves its characteristic sleep entrainment by the age of 3 months. The arcuate nucleus of the hypothalamus contains neurons that secrete GH-releasing hormone (GHRH) when stimulated by norepinephrine and serotonin. In contrast, somatostatin (GH release–inhibiting hormone [abbreviated ss]) is synthesized by neurons in the hypothalamic paraventricular nucleus and other brain centers. Somatostatin inhibits GH secretion both directly at the somatotrope level and indirectly by suppressing GHRH release. In turn, both GHRH and GH stimulate somatostatin release, thereby turning off the GH secretion. GH also inhibits GHRH release in a short negative feedback loop. Pulses of GH occur when the brain enters stage IV sleep, a time of GHRH release and somatostatin withdrawal.
The GH pulses reach their greatest amplitude during puberty, a central effect of estrogen in both genders. Similarly, circulating levels of GH in females peak at the time of ovulation due to the estrogen-stimulated increase in frequency of the GH pulses. GH synthesis is itself highly regulated. Expression of the pituitary GH gene, one of five closely related genes on chromosome 17q22-24, requires the pituitary transcriptional factor, Pit1. It is also stimulated by GHRH and thyroid hormone (T3) and repressed by cortisol. Somatostatin does not affect GH synthesis, only its secretion. During transcription, alternative mRNA splicing results in 22- and 20-kDa GH isoforms, both of which circulate and stimulate linear growth. GH circulates bound to serum binding proteins, especially the GH-binding protein (GHBP), which is the extracellular domain of the GH receptor (GHR). GH is released from the circulation to bind to its receptor, GHR, located in multiple target tissues and primarily the liver. A member of the cytokine receptor superfamily, GHR is a single-chain glycoprotein with a single transmembrane domain that activates the intracellular JAK/STAT signaling pathway. The number of hepatic GHRs increases postnatally, during puberty, and during pregnancy, another effect of estrogen. In addition to modulation of the number of GHRs, GH sensitivity can be regulated by an intracellular negative feedback loop; GH induces suppressors of cytokine signaling (SOCs) that inhibit GH-induced activation of the GHR/JAK2 complex. According to the somatomedin hypothesis, GH actions are mediated by its stimulation of hepatic insulin-like growth factor (IGF)-I synthesis and release. It is now understood that GH has direct effects on target tissues independent of IGF-I and that IGF-I release can be both endocrine (hepatic) and autocrine/paracrine (locally within the target tissues). GH stimulates not only IGF-I production by the hepatocytes but also production of the acid-labile subunit (ALS) by hepatocytes and the IGF-binding protein (IGFBP)-3 by hepatic endothelia and Kupffer cells. All three proteins are released into the circulation as a 150-kDa complex. This complex is believed to prolong the half-life of circulating IGF-I and to control its delivery to the target tissues where it binds and activates the IGF receptor (IGF-1R). IGF-1R is a tyrosine kinase receptor, similar to the insulin receptor, that promotes cellular survival and mitogenesis. IGF-I provides additional negative feedback loops decreasing GH secretion, both directly at the somatotrophs and indirectly at the hypothalamus through stimulation of somatostatin. A new GH-releasing factor, Ghrelin, was identified and cloned. Ghrelin is an octanoylated 28–amino acid peptide synthesized primarily by the X/A-like cells of the stomach. Ghrelin was discovered to be the endogenous ligand for the GH secretagogue receptor (GHS-R), a seven-transmembrane
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domain, G protein–coupled receptor that is expressed in the hypothalamus, pituitary, and other brain centers. In a study of seven healthy men, aged 24 to 32 years, stimulation of GH release was significantly greater by Ghrelin than GHRH, and synergistic when both agents were administered. Ghrelin has also been shown to potently induce feeding behavior, through the c-fos, neuropeptide Y, and agouti-related peptide pathways. It is not surprising that a stomach product should stimulate GH secretion, as there are numerous connections between the GH axis and the metabolic status of the body. GH secretion is often blunted by obesity, glucose, and free fatty acids, whereas hypoglycemia and certain amino acids stimulate GH release. The number of hepatic GHRs decreases with fasting but increases with refeeding; their number is quickly modulated through internalization and microaggregation into coated pits. IGF-I production is very sensitive to nutritional status, especially protein and, to a limited extent, total caloric intake. The amount of circulating free IGF-I is further influenced by metabolic effects on IGFBP production, most notably suppression of hepatic IGFBP-1 by insulin. Conversely, GH exerts multiple metabolic effects apart from its stimulation of somatic growth. GH is an anabolic, insulin counterregulatory hormone, that stimulates lipolysis, promotes protein anabolism, lowers circulating total and LDL cholesterol levels, increases cardiac output, and improves bone mineralization. For these metabolic reasons, the Food and Drug Administration has approved GH replacement therapy for GH-deficient adults, even though they can no longer grow.
The Growth Plate The growth of long bones occurs at the growth plate through a highly regulated sequence of chondroplasia and osteogenesis (Figure 8-2). Grossly, bone growth occurs in the
Figure 8-2
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direction toward the epiphysis, whereas the process at the cellular level proceeds in the opposite direction. Chondroplasia occurs in the reserve, proliferative, and upper hypertrophic zones of the growth plate. Prechondrocytes, the cartilage precursor cells, in the reserve zone differentiate into chondrocytes in a GH-dependent manner. Young chondrocytes then undergo clonal expansion (four cell divisions each) in the proliferative zone under IGF-I stimulation. In fact, part of the GH-induced differentiation of prechondrocytes into chondrocytes involves the expression of new genes like IGF-I, IGF-1R, and the estrogen receptor. After proliferation, the chondrocytes elongate in the upper hypertrophic zone under both GH and IGF-I influences. This elongation contributes about 60% of total growth, versus only 15% from the preceding cellular proliferation. In the lower hypertrophic zone, the chondrocyctes begin to produce a calcified matrix. The cells become entrapped and die by apoptosis within 4 days. They leave behind lacunae, which are penetrated by bone marrow in the resorption front. Ultimately, the lacunae are inhabited by osteoblasts and osteoclasts. The bone marrow is very rich in GHR. GH recruits osteoclasts from bone marrow monocytes and stimulates paracrine IGF-I production, which then leads to white blood cell proliferation. In addition to its central involvement in GH secretion, thyroid hormone is required at the growth plate for osteogenesis to occur. The mechanism whereby estrogen fuses the growth plate is still unknown. Bone growth is also highly sensitive to biomechanical forces. For example, the strength of healthy load-bearing bones correlates with muscle strength, and the length of congenitally paralyzed limbs grows less than their nonparalyzed counterparts through postnatal mechanical effects on chondral modeling. The Utah paradigm of skeletal physiology examines the impact of biomechanical forces, especially muscular factors, on cartilage physiology and skeletal development.
Growth at the Growth Plate. Growth of long bones occurs at the growth plate, seen grossly as bone elongation toward the epiphysis. The cellular events progress in the opposite direction, from chondroplasia through osteogenesis, under coordinated regulation by several hormones. GH, growth hormone; IGF-I, insulin-like growth factor I; E2, estrogen; T3, thyroid hormone. (Based on Hochberg Z: Clinical physiology and pathology of the growth plate. Best Pract Res Clin Endocrinol Metab 2002;16:399 with permission.)
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GROWTH EVALUATION The study of growth can be seen from three different perspectives. The first is the basic scientific study of growth per se. The second perspective is the use of growth as an index of the health and condition of society. This perspective is embodied in population surveys such as those of the U.S. National Center for Health Statistics (NCHS). The third perspective involves the study by the clinician of the growth of an individual patient. The routine measurements of weight and length at birth were first introduced in a Paris hospital in 1800, but it was not until 80 years later when the systematic following of infants in their first and second years was established. Growth is a sensitive indicator of a child’s health. Therefore, frequent and accurate assessment of growth as part of routine health maintenance is of primary importance in children. Understanding the normal patterns of growth is a prerequisite to the diagnosis of growth disorders. Growth is a complex process and involves the interaction of multiple factors previously described in this chapter. Despite this complexity, children normally grow in a remarkably predictable manner. Deviation from the normal pattern of growth is frequently the first manifestation of a wide variety of disorders that is discussed later in this chapter.
Phases of Normal Growth At each stage of life, from intrauterine development to the cessation of growth in adulthood, growth occurs at different rates. To better understand the process of growth, it is important to distinguish the different and partially superimposable phases of growth (Box 8-1). Prenatal Growth
The most dramatic events in growth occur before birth, the transformation of a single cell into an infant. Prenatal growth varies dramatically, averaging 1.2 to 1.5 cm/wk. The
Box 8-1
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Prenatal growth Infancy Childhood Puberty
1.2 to 1.5 cm/wk 23 to 28 cm/yr 5 to 6.5 cm/yr 8.3 cm/yr (girls) 9.5 cm/yr (boys)
velocity of linear growth reaches a peak at about 18 weeks of gestation, when the fetus is growing at a velocity of 2.5 cm/wk, and falls to almost 0.5 cm/wk immediately before birth. Growth in weight follows the same pattern, except that the peak is reached later. There is a difference in average length between boys and girls of around 0.8 cm by 30 weeks of gestation and 1 cm by 40 weeks. This difference is due to a slightly faster growth in boys since early in fetal life. Growth during the last few weeks of gestation slows down significantly due to the influence of uterine size, so that size at birth reflects the maternal environment more than genetic influences. After birth the growth rate increases again, and genetically large children catch up to their programmed curves in the 6 to 12 months after birth. In the same way, genetically small children slow down to follow their curves. Intrauterine growth retardation, which can result from many different causes, can have a lasting effect on a child’s growth throughout life. Regardless of the etiology, retardation in fetal growth when fetal growth is very rapid during early pregnancy may result in persistent postnatal growth impairment. Growth During Infancy
After birth, the infant shifts from a growth rate that is predominantly determined by maternal factors to one that is increasingly related to his or her own genetic background, as reflected by midparental size (Box 8-2). Consequently, for about two thirds of normal infants, the linear growth rate shifts during the first 12 to 18 months. Thus, during the first year of life, growth velocity is rapid and highly variable, averaging 23 to 28 cm/yr. During this period, growth velocity is independent of endogenous GH. Prenatal influences on growth may continue, so the small-for-gestational age (SGA) neonate who has the genetic capacity to catch up to the normal range generally shows accelerated growth within the first 6 months after birth. In contrast, most SGA babies who do not show catch-up growth during the first 6 months continue to grow at a slow rate into childhood and are generally destined to be of small stature. Those who are relatively large at birth but whose genetic background is for smaller size tend to grow more slowly, as a physiological effort to balance the genetic and environmental components of growth.
Box 8-2
Calculating Mid-Parental Height
For boys: Father’s height + (mother’s height + 13 cm)/2 For girls: Mother’s height + (father’s height − 13 cm)/2
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Growth During Childhood
During the second and third years of life, growth velocity declines rapidly, averaging 7.5 to 13 cm/yr. Longitudinal studies of the first 2 years after birth show that the differential between boys’ and girls’ growth velocities diminishes during the first year, until during the second year when the girls’ velocity is actually greater. By the end of the third year, growth rate has settled into a steady, consistent pattern that persists throughout the childhood years until puberty. On average, a healthy child grows at a velocity of approximately 5 to 6.5 cm/yr during the childhood years and usually does not deviate significantly from this pattern until the onset of puberty. Growth chart maintenance at regular intervals helps to establish the individual growth pattern relative to normative data and facilitates assessment when a meaningful change in growth pattern occurs. Growth During Puberty
Puberty plays a dual role in growth: height velocity is markedly accelerated; the rate of skeletal maturation is also increased with resultant fusion of epiphyseal cartilage. Thus puberty can be considered as a growthpromoting event as well as the final height-limiting process. Several hormonal factors may interact to determine the pubertal growth spurt: GH, IGF-I, and sex steroids of gonadal and adrenal origins. In both sexes, the role of gonadal steroids is obvious from the remarkable acceleration of linear growth that occurs at the time of sexual maturation, whether that event is early, normal, or delayed. In the absence of normal GH and IGF-I secretion, gonadal steroids have limited growth-promoting effects. This is suggested by the subnormal increase of the growth rate in hypopituitary boys treated with testosterone before GH therapy was available. Additional evidence for the effects of sex steroids in the absence of GH action is obtained from patients with Laron dwarfism. Among eight of these patients followed throughout puberty, three girls did not show any significant growth spurts. In contrast, in three boys and two girls who grew at a mean rate of 2.9 cm/yr before puberty, height velocity increased to 6.5 cm/yr during sexual maturation. These observations suggest that sex steroids may have a direct growth effect independent of GH and IGF-I. Nonetheless, the acceleration of growth caused by sex steroids in the absence of normal GH and IGF-I is minimal compared with the normal pubertal spurt. In patients with sex steroid deficiency and normal GH secretion, no pubertal growth spurt occurs. Patients with congenital hypogonadism have a normal pattern of prepubertal growth. However, no obvious pubertal growth spurt occurs in GH-treated boys with gonadotropin deficiency
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unless sex steroids are also administered. Numerous researchers have shown that sex steroids, especially estrogens, modulate GH secretion, in particular, increasing the amplitude of GH secretory episodes. GH in turn stimulates IGF-I production, accounting for or reflecting the increased growth velocity. The onset of puberty brings a rapid growth velocity, but frequently, this acceleration in growth may be preceded by an apparent slowing down or falling off of the individual growth curve. Pubertal growth begins earlier in girls than in boys but is 3 to 5 cm greater in magnitude in boys than in girls. The adult sex difference, averaging 13 cm, is due mainly to the earlier termination of growth in girls. Boys have 2 years more in which to grow before entering puberty. Thus boys, when their puberty starts, are about 8 to 10 cm taller than girls when their puberty started 2 years earlier. The boys’ larger pubertal spurts add the remaining differences. The peak height velocity during the pubertal growth spurt is comparable with the rate of growth during the second year of life. The average peak height velocity is 8.3 cm/yr in girls and 9.5 cm/yr in boys. The time of onset of the pubertal growth spurt varies in normal children, reflecting the concept of a “tempo of growth” or rate of maturation, as emphasized by Tanner. The physiological basis for differences in tempo among individuals is unknown but it appears to have genetic influences. Tempo and final height are practically unrelated in normal children. Whether the pubertal growth spurt occurs early or late exerts little influence on final height in most normal boys and girls. This statement does not necessarily hold for children with true precocious puberty. In both sexes, sexual precocity increases the immediate growth rate and the total pubertal height gain, compared with average maturers. There is increased duration of puberty, which increases the total pubertal height gain, but the increased rate of bone maturation markedly reduces the period of prepubertal growth so that the net effect is final height loss. In both sexes, delayed puberty reduces the immediate growth rate and the total pubertal height gain, compared with average maturers. Also, there is, at least in boys, a reduced duration of puberty. However, the reduced rate of bone maturation increases the prepubertal height gain so the final height is not affected. Growth ceases when the skeleton achieves adult maturity. The vertebral column continues to grow for a while after the limbs have stopped, as do shoulder and chest widths. Whether growth has finished cannot be judged from chronological age. Often auxologists take an increment of less than 1 cm over one full year as an indicator of the end of growth, but some data indicate that after this there is an average further gain of 1 cm.
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Measurement Accurate and reproducible measurements of height are essential for monitoring growth. Individual measurements at a single point in time detect absolute short or tall stature, but two or more measurements over a period of time are needed to detect a change in growth velocity, regardless of the starting height. The guidelines of the American Academy of Pediatrics state that children should be measured every 2 months until age 6 months, every 3 months from age 6 to 18 months, and then yearly until age 18 years. Effective growth monitoring needs precise measurement, accurate plotting on appropriate charts, and correct interpretation. Although measuring techniques have improved during the past two decades, recent studies of routine child measurement techniques in pediatric practices throughout the United States have shown severe deficiencies. Measuring height is subject to error as a result of poor technique, variations between instruments and observers, movement of the child, diurnal variations, and plotting mistakes. Incorrect measurements may result in failure to identify growth pathology or in apparent deviations for a child who is actually growing normally. Supine length is routinely measured during the first 24 months, whereas erect height is assessed in older children. Between 24 and 36 months, measurements can be made on children in either a recumbent or standing position. It is important to plot the child using the appropriate growth chart depending on whether a supine or an erect height was obtained; a child’s standing height is less than his or her length, and plotting height on a length chart will give the false perception that growth has decelerated. For measurement of supine length, it is best to use a firm box with an inflexible board against which the head lies, with a movable footboard on which the feet are placed perpendicular to the plane of the supine length of the infant. The use of cloth or plastic measuring tapes should be avoided. Correctly measuring a neonate or infant is a two-person job. Optimally, the child should be relaxed, the legs should be fully extended, and the head should be positioned in the “Frankfurt plane” with the line connecting the outer canthus of the eyes and the external auditory meatus perpendicular to the long axis of the trunk. The infant should be gently stretched. The footplate should be placed against the feet, making sure the toes are vertical to the heels. When children are old enough to stand erect, it is best to use a stadiometer to determine height. Swinging or floppy arm devices can result in grossly inaccurate readings due to the angle of the arm to the measuring device, in addition to the positioning and posturing of the child. A stadiometer consists of a moving headplate (placed at a precise 90-degree
angle to the wall) and a metal measuring tape. There are different models of stadiometers, but essentially any device that meets the requirement of a completely flat wall, precise 90degree angles at both feet and head, and an accurate metal measuring tape can provide accurate, reproducible measurements of growth, provided appropriate measuring techniques are used. To appropriately measure a standing child, the child should stand up straight, heels together, toes comfortably apart, and the head aligned in the Frankfurt plane. The heels, back of legs, buttocks, shoulders, and occiput should touch the vertical surface of the stadiometer or the wall. The lordotic curve in the lumbar region can be minimized by having the child relax the shoulders. Additionally, the measurer can gently press the abdomen toward the wall to reduce the space between the lower back and the wall. The head should be level, with the child looking straight ahead stretched upward to compensate for diurnal height variations. The individual doing the measuring can accomplish this by placing his or her hand beneath the angle of the child’s jaw and lifting gently. To eliminate the effect of diurnal variation, measurements should be taken at or near the same time of the day. A reduction in stature averaging about 8 mm has been found during the first hour after rising from bed. During the next hours, the shrinkage is less, around 6 or 7 mm during the rest of the day. Virtually all the decrease is accounted for by sitting height, and it is primarily due to fatigue of the muscles of the spine. Taking three consecutive measurements and recording the mean value is one method of increasing the accuracy of growth measurements. Other measurements that are important in the evaluation of a child with short stature but not necessarily for routine growth follow-up include sitting height and limb measurements. Sitting height is important in the differential diagnosis of short stature, particularly in relation to chondrodystrophies, and is also important in the follow-up of children treated with spinal irradiation. Limb segment measurements are also useful in the differential diagnosis of chondrodystrophies. The measurement of knee height (the distance from the upper surface of the knee to the lower surface of the heel) is useful when growth velocity is determined during a short period of time and in the study of fluctuations in growth rate, as it is more sensitive to shortterm changes than statural height.
Growth Charts A long list of heights and weights is very difficult to interpret, so numerical values should always be plotted on a growth chart. The original measurements should also be recorded because it is easy to make plotting errors. When plotting a child’s height, it is important to use the appro-
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priate growth chart (according to gender) and to adequately plot the age of the patient. It is not a good practice to round off the age of the patient to the closest year; the age should be plotted as accurately as possible. Growth charts allow us to compare the growth of an individual child with the growth of a standardized group of children who are believed to be healthy. Thus growth charts are very useful tools in child health surveillance, and their proper use and understanding are essential. Growth charts fall into several categories, which include distance charts, velocity charts, cross-sectional charts, and longitudinal charts. In distance charts, stature is plotted against age, and they can be of the cross-sectional or longitudinal type. The second category of charts, velocity charts, plot annual increments. These charts are tempo conditioned, in that they allow for the variations in timing and intensity of the adolescent growth spurt. The velocity in many ways reflects the child’s state at any particular time better than the distance, which represents the accumulation of events in all of the preceding years. For cross-sectional charts, the data are collected from the entire age range and a large sample of different children is used in each age band. In the longitudinal (individual) charts, the shape of the curve is derived from data collected from a relatively small sample of children followed over several years. Most of the charts used currently are based on cross-sectional population studies. The data on which the charts are based should relate to the population under consideration and should be updated at regular intervals. Distance and Velocity Standards
Evaluation of a child’s height must be performed in the context of normal standards. The NCHS publishes several growth charts, with separate charts for boys and girls appropriate for ages birth to 36 months and 2 to 20 years (Figures 8-3 through 8-6). During the transition from one growth chart to another, which usually occurs between 2 to 3 years of age, there may be an apparent discontinuity in the percentile of the child’s growth. This is caused by the shift in measurements taken standing versus lying down. These charts compare individual children with the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of normal American children but do not satisfactorily define children below the 5th or above the 95th percentile. NCHS released new growth charts in 2000 that are not only updated but also more representative of the American population, more accurately reflecting the nation’s cultural and racial diversities. The charts are based on data gathered through the National Health and Nutrition Examination Survey (NHANES), the only survey that includes data from actual physical examinations on a cross section of Americans from all over the country. Charts based on cross-sectional data do
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not take into account that time of puberty and therefore acceleration of linear growth varies from child to child. Some charts have been developed by Tanner and colleagues to address this issue (Figures 8-7 and 8-8). Such charts are of particular value in assessing growth during adolescence and puberty and for plotting sequential growth data on any given child. Properly used, velocity standards are far superior to distance standards for rapidly picking up abnormalities. Velocity measures what has happened during the past year or 6 months, whereas distance measures the whole accumulated experience of childhood. Although there is considerable variability in the normal height velocity in children of different ages, between the age of 2 years and the onset of puberty children normally grow with remarkable fidelity relative to the normal growth curves. Any “crossing” of height percentiles during this age period should be noted and investigated, and abnormal height velocity always warrants further evaluation. Growth velocity is calculated using a minimum of two measurements, obtained across time, with the plotted data point representing the mean growth velocity achieved during the interval, as opposed to the measurable increment between the two time points. Growth velocity charts are useful in identifying a growth pattern reflecting the individual’s achieved growth velocities over time compared with normal standards (Figures 8-9 and 8-10). Charts for Children With Growth Pathology
There are charts available for certain genetic syndromes, including Turner syndrome (Figure 8-11), achondroplasia, and Down syndrome (Figures 8-12 through 8-15). Such growth profiles are invaluable for tracking the growth of children with these clinical conditions. The charts are used in essentially the same way as the charts for normal children. Deviation of growth from the appropriate diseaserelated growth curve suggests the possibility of a second underlying problem. For example, children with Down syndrome have a higher incidence of hypothyroidism (congenital and autoimmune), which can further impair their growth; thus, a deviation from their pattern of growth may be the first diagnostic clue.
Parental Target Height Because genetic factors are important determinants of growth and height potential, it is useful to assess a patient’s stature relative to that of siblings and parents. Although during the first 18 months to 2 years, the height of a child is not closely related to parental heights, by age 2 the correlation becomes sufficiently high for knowledge of parental height to lend a considerable increase in precision Text continued on page 147
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Figure 8-3
Growth Chart for Boys from Birth to 36 Months. Published May 30, 2000 (modified 4/20/01). Source: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http://www.cdc.gov/growthcharts
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Figure 8-4 Growth Chart for Girls from Birth to 36 Months. Published May 30, 2000 (modified 4/20/01). Source: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http://www.cdc.gov/growthcharts
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Figure 8-5
Growth Chart for Boys from 2 to 20 Years. Published May 30, 2000 (modified 11/21/00). Source: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http://www.cdc.gov/growthcharts
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Figure 8-6 Growth Chart for Girls from 2 to 20 Years. Published May 30, 2000 (modified 11/21/00). Source: Developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). http://www.cdc.gov/growthcharts
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Figure 8-7 Boys’ Tanner Chart. (From Tanner JM, Davis PSW: Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;144:267, The CV Mosby Company, Copyright 1985. Reproduced with permission Castlemead Publications.)
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Figure 8-8
Girls’ Tanner Chart. (From Tanner JM, Davis PSW: Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;144:267, The CV Mosby Company, Copyright 1985. Reproduced with permission Castlemead Publications.)
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Figure 8-9 Boys’ Velocity Chart. (From Tanner JM, Davis PSW: Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;144:267, The CV Mosby Company, Copyright 1985. Reproduced with permission Castlemead Publications.)
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Figure 8-10 Girls’ Velocity Chart. (From Tanner JM, Davis PSW: Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 1985;144:267, The CV Mosby Company, Copyright 1985. Reproduced with permission Castlemead Publications.) 141
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Figure 8-11 Growth Chart for Girls with Turner Syndrome. The top three lines represent normal girls; the remaining lines represent untreated Turner patients. (From Lyon AJ, Preece MA, Grant DB: Growth curve for girls with Turner syndrome. Arch Dis Child 1985;60:932, BMJ Publishing Group, copyright 1985.) 142
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Growth Chart for Boys with Down Syndrome from 1 to 36 Months. (Reproduced
with permission from Pediatrics 1988;81:102-110, Figures 5, 6, 7, and 8, copyright 1988.)
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Girls with Down Syndrome: Physical Growth: 1 to 36 Months 42 41
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AGE (MONTHS)
kg B
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Figure 8-13
6
9
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Growth Chart for Girls with Down Syndrome from 1 to 36 Months. (Reproduced
with permission from Pediatrics 1988;81:102-110, Figures 5, 6, 7, and 8, copyright 1988.)
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Boys with Down Syndrome: Physical Growth: 2 to 18 Years 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 in
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Figure 8-14
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Growth Chart for Boys with Down Syndrome from 2 to 18 Years. (Reproduced with
permission from Pediatrics 1988;81:102-110, Figures 5, 6, 7, and 8, copyright 1988.)
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Girls with Down Syndrome: Physical Growth: 2 to 18 Years 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 in
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AGE (YEARS) 3
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Figure 8-15
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Growth Chart for Girls with Down Syndrome from 2 to 18 Years. (Reproduced with
permission from Pediatrics 1988;81:102-110, Figures 5, 6, 7, and 8, copyright 1988.)
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15
15 30 kg lb 18
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Disorders of Growth
in determining appropriate heights for an individual child. The child’s predicted adult height may be related to a parental target height or the mathematical average of the parents’ heights with the addition or subtraction of 6.5 cm for boys and girls, respectively. Most children achieve within ±2 SDs of their midparental height, assuming the normal process of heredity and approximately similar environmental effects on growth in both generations. The 2-SD range for this calculated parental target height is about ±10 cm. For plotting purposes, on a boy’s chart, the father’s height is plotted straightforwardly, but the mother’s height has to be approximately adjusted by adding 13 cm; this represents the average adult sex difference. In plotting the father’s height on a girl’s chart, 13 cm must be subtracted. The value midway between the father’s and mother’s plots represents the midparental height. Nevertheless, when a child’s growth pattern deviates from that of parents or siblings, the possibility of an underlying pathological condition should be considered. When using parental height to evaluate a child’s pattern of growth, there are some caveats. First, most of the time the parents’ heights are obtained by their report and not by actual measurement, which often induces inaccuracies. Second, we assume that both of the parents grew up in environments that did not restrict their growth. Actual pathology in one or other of the parents disqualifies the use of their measurements. Parental pubertal patterns provide the physician with insights into the likelihood that a child will enter puberty early or late in life. It is therefore important to obtain this information in addition to the parents’ heights. Box 8-2 contains the formulas to calculate midparental heights in boys and girls.
Skeletal Maturation and Prediction of Adult Height An estimate of tempo of growth and maturation is often important in the diagnosis and treatment of growth disorders, and the only available measurement at all ages from birth to adulthood is skeletal maturity, or bone age. The bone age represents an index of maturation that relates more closely than chronological age to growth. This is particularly obvious for patients who deviate significantly from the normal tempo of growth and puberty. The growth potential in the tubular bones can be assessed by evaluation of the progression of ossification within the epiphyses. The ossification centers of the skeleton appear and progress in a predictable sequence in normal children, and skeletal maturation can be compared with normal age-related standards. It is not completely clear what factors determine this normal maturation pattern, but genetic factors and multiple hormones, including thyroxine, GH, and gonadal
147
steroids, are involved (see Figure 8-2). During puberty, estrogen is the main determinant of skeletal maturation. After the neonatal period, a radiograph of the left hand and wrist is commonly used for comparison with the published standards of Greulich and Pyle. Greulich and Pyle’s Radiographic Atlas of Skeletal Development consists of two parts. The first contains two series of hand/wrist radiographs, one for boys and another for girls. Each radiograph is labeled with a skeletal age. The second part consists of drawings and descriptions of the successive stages of development of each of the individual bones, with bone ages assigned to each stage. The recommended method to evaluate the bone age using the Greulich and Pyle atlas is a bone-by-bone assessment, followed by final use of the mean age of all ratable bones. Bone age is an index of somatic maturation, and the skilled interpretation of bone age radiography can indicate with some accuracy the amount of bone growth remaining. Because the evaluation of bone age films is not a straightforward process, it may be convenient for the primary care physician to identify a radiologist with experience in reading and interpreting bone age films. Obviously, final height cannot be determined until epiphyseal cartilages have closed. Because it takes such a long time to attain final height, in the clinical setting we attempt to predict the ultimate stature of patients to evaluate the likely effects of therapeutic modalities. The extent of skeletal maturation observed in an individual can be used to predict the ultimate height potential. Height gain during a given period of life is directly related to the increment in height and inversely related to the advancement in the bone age. Predictive evaluation of any endocrine condition or therapy on ultimate height must rely on studies of the rate of linear growth versus the rate of bone maturation. The prediction is based on the observation that the more delayed the bone age (relative to the chronological age), the longer is the time before epiphyseal fusion precludes further growth. The estimate of predicted adult height is useful both at the time of diagnosis of growth pathology for comparison with parent target range and during treatment. There are several methods to predict adult height, but the most commonly used one, based on Greulich and Pyle’s, atlas, was developed by Bayley and Pinneau and relies on bone age, height, and a semiquantitative allowance for chronological age. The more advanced the bone age, the greater is the accuracy of the adult height prediction because a more advanced bone age places a patient closer to final height. Final height predictions are less accurate in patients showing marked deviations from the range of physiological variations in height or marked differences between bone age and chronological age. All methods of predicting adult height are based on data from normal children and do
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PEDIATRIC ENDOCRINOLOGY: THE REQUISITES IN PEDIATRICS
not accurately predict adult height in children with growth abnormalities. The predicted adult height of the child being evaluated is compared with the target range. If it falls anywhere within the range, the child is likely to be normal.
SHORT STATURE/GROWTH FAILURE The Clinical Problem The prospect of short stature worries parents, children, and pediatricians. “Heightism” refers to the psychosocial prejudice and discrimination against shorter individuals. The severity of heightism depends on both the degree of statural deficit and the general level of social tolerance in the local culture. The average heights of men and women in the United States, according to the 2000 National Center for Health Statistics, are 5 feet 9.5 inches and 5 feet 4 inches, respectively. Tall stature has been associated with success in multiple social arenas, as exemplified by salary and recruitment profiles, outcomes of presidential elections, life insurance policy values, and the social mores of men always being taller than their romantic partners. In one of the largest studies on heightism, all Swedish men born in 1976 and conscripted in 1994 were evaluated, excluding only those with growth-affecting disorders or missing data (final subject population, 32,887). Conscripts whose heights fell below −2 SDs were found to (1) have more psychiatric and musculoskeletal diagnoses, (2) more often be considered psychologically unsuitable for military service and less suitable for leadership positions, and (3) score lower on intellectual tests and assessments of psychological functioning during mental stress. Two psychological phenomena may contribute to this outcome. First, by the halo effect, a person with one desired trait is assumed to possess other desired traits. Thus, short individuals enter each and every social interaction with one strike against them based on first impression. Because the desired physical trait is height in males but beauty in females, heightism affects males more than it does females. Also, in children, physical size is often interpreted as the main clue to their chronological age. Thus, an 8-year-old who is the size of an average 6-year-old is often treated by adults as a 6-year-old; the 8-year-old thereby loses out on the social, emotional, and cognitive developmental challenges and responsibilities appropriate to his or her age. However, growth failure has significant medical implications far beyond the psychosocial aspects of heightism. Growth is the single most sensitive sign that something is amiss with a child. It is also very nonspecific. Consequently, as expanded in the following sections, the differential diagnosis of growth failure is as broad as the field of general pediatrics. Looking at it from another perspective, growth
failure is often the first and only sign of an underlying medical process. Prompt recognition, diagnosis, and treatment of the underlying pathophysiological process are equally imperative in children of both genders. “Short stature” is defined as height below −2 SDs for age and gender (i.e., less than the third percentile for the population). “Dwarfism” refers to severe short stature, less than −3 SDs. “Midgets” have normally proportioned short stature. Inherent to these definitions is the comparison with an appropriate reference population. Along the same lines, growth failure can be defined as height less than 2 SDs below the parental target height. Thus, a child whose height is on the 25th percentile for age and gender of the general population may still have clinically significant growth failure if his or her genetic potential is at the 90th percentile. An abnormally slow growth velocity is another indication of growth failure. Between age 3 years and puberty, a growth rate below 5 cm/yr (2 in/yr) should prompt attention. Consequent to an abnormally slow growth velocity, downward crossing of percentile channels on the growth chart constitutes yet another definition of growth failure. This especially holds true after the age of 18 months. Before that age, many infants change channels from their birth size, which is primarily determined by extrinsic factors (pregnancy health, placental sufficiency, maternal health), to their own intrinsically determined curve, which they will track into adulthood. Whenever a child fulfills one of these definitions, summarized in Box 8-3, the differential diagnosis of growth failure should be investigated.
Differential Diagnosis of Short Stature/Growth Failure Healthy but Short Children
Two main subgroups comprise the vast majority of short children, and neither indicates a pathological process (Box 8-4). Familial short stature (FSS) refers to normal growth
Box 8-3
Definitions of Growth Failure
• Height below third percentile (−2 SDs for age and gender) • Height significantly below genetic potential (−2 SDs below mid-parental target)
• Abnormally slow growth velocity (10 mg/dL
